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Oncoimmunology. Oct 1, 2012; 1(7): 1111–1134.
PMCID: PMC3494625

Trial watch

Dendritic cell-based interventions for cancer therapy
Lorenzo Galluzzi, 1 , 2 , Laura Senovilla, 2 , 3 , 4 , Erika Vacchelli, 2 , 3 , 4 , Alexander Eggermont, 2 Wolf Hervé Fridman, 1 , 5 , 6 , 7 Jerome Galon, 1 , 5 , 6 , 7 , 8 Catherine Sautès-Fridman, 1 , 6 , 8 Eric Tartour, 9 , 10 Laurence Zitvogel, 2 , 11 and Guido Kroemer 1 , 4 , 6 , 9 , 12 ,*

Abstract

Dendritic cells (DCs) occupy a central position in the immune system, orchestrating a wide repertoire of responses that span from the development of self-tolerance to the elicitation of potent cellular and humoral immunity. Accordingly, DCs are involved in the etiology of conditions as diverse as infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. During the last decade, several methods have been developed to load DCs with tumor-associated antigens, ex vivo or in vivo, in the attempt to use them as therapeutic anticancer vaccines that would elicit clinically relevant immune responses. While this has not always been the case, several clinical studies have demonstrated that DC-based anticancer vaccines are capable of activating tumor-specific immune responses that increase overall survival, at least in a subset of patients. In 2010, this branch of clinical research has culminated with the approval by FDA of a DC-based therapeutic vaccine (sipuleucel-T, Provenge®) for use in patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer. Intense research efforts are currently dedicated to the identification of the immunological features of patients that best respond to DC-based anticancer vaccines. This knowledge may indeed lead to personalized combination strategies that would extend the benefit of DC-based immunotherapy to a larger patient population. In addition, widespread enthusiasm has been generated by the results of the first clinical trials based on in vivo DC targeting, an approach that holds great promises for the future of DC-based immunotherapy. In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating DC-based interventions for cancer therapy.

Keywords: CD8+ cytotoxic T lymphocytes, Provenge®, Toll-like receptors, antigen-presenting cells, immunotherapy, pulsed dendritic cells

Introduction

In 1973, Ralph Steinman and colleagues were the first to report that murine lymphoid organs, notably the spleen, contain a small population of cells exhibiting a very peculiar tree-like morphology, which they named (after the Greek term ‘dendron’, meaning tree) dendritic cells (DCs).1 Since then, thanks to the work of other pioneers of the field including (but not limited to) Anna Karolina Palucka and Jacques Banchereau,2-18 the structural and functional features of murine and human DCs have been characterized with increasing precision, and DCs have turned out to occupy a central position in the immune system. Indeed, DCs are able to orchestrate a wide repertoire of immune responses, spanning from the development of self-tolerance to the elicitation of potent cellular and humoral antigen-specific immunity. This is due to 4 main features that are a prerogative of DCs: (1) their localization at sites of intense antigen exposure; (2) their competence to engulf, process and present to T cells large amounts of antigens; (3) their ability to respond to a plethora of stimuli, and (4) their capacity to mature into multiple, functionally-distinct subsets.19 Due to its pioneer discoveries on DCs, Ralph Steinman has been awarded—posthumously, for the first time in history—the 2011 Nobel Prize for Medicine and Physiology.20

DCs derive from bone marrow progenitors and can be found in virtually all tissues, but are highly enriched where antigen exposure is more intense such as in lymphoid organs, at the body surface (i.e., skin, pharynx, esophagus, vagina, ectocervix and anus) as well as at internal mucosae (i.e., respiratory system and gastrointestinal tract).19,21 DCs exhibit peculiar probing movements (relentlessly forming and retracting cellular processes from distinct areas of the cell body), which allow them to continuously monitor the microenvironment for the presence of antigens. Antigen uptake can occur in situ, followed by the migration of DCs to draining lymph nodes via afferent lymphatics,22 or directly within lymph nodes, when soluble antigens reach resident DCs through the lymph.23 Of note, distinct immune responses can be elicited by DCs depending on the specific site at which antigens are taken up.23 This reflects the remarkable functional heterogeneity of DCs (see below).

Tissue-resident DCs normally are immature, i.e., they have a high capacity for antigen uptake but a limited potential for releasing cytokines, and they express (1) MHC Class II molecules mostly in the late endosome-lysosomal compartment, (2) low levels of co-stimulatory molecules (e.g., OX40L, CD40, CD70, CD86) and (3) particular chemokine receptors.20 Of note, immature DCs (iDCs) do not necessarily mature once they take up antigens, as maturation requires a complementary set of signals from the microenvironment. Importantly, in the absence of such signals, iDCs efficiently present antigens to T cells in the context of inhibitory interactions. This response, which appears to be critical for the development of peripheral self tolerance, can be mediated by two distinct mechanisms, namely, the deletion of antigen-specific T cell clones (clonal deletion) and the expansion of CD4+CD25+FOXP3+ regulatory T cells (Tregs).24 The former has been shown to depend on the expression by DCs of surface cell death-inducing molecules such as FASL25,26 and PD-L1.27 Conversely, the latter appears to proceed (at least in part) indirectly, following the release of interleukin (IL)-2 by conventional CD4+ cells that would interact — in a MHC Class II-dependent fashion — with DCs.28

iDCs can mature, hence becoming able to elicit adaptive T cell-based immunity, in response to a wide array of environmental signals including microbe-associated molecular patterns (MAMPs, e.g., lipopolysaccharide, unmethylated CpG DNA, double-stranded RNA), damage-associated molecular patterns (DAMPs, e.g., ATP, uric acid, HMGB1, heat-shock proteins), immune complexes as well as cytokines/chemokines released by neighboring immune or stromal cells. These paracrine mediators include, but are not limited to, interferon (IFN) γ, which can be secreted by γδ T cells as well as by natural killer (NK) cells; IL-4 and tumor necrosis factor α (TNFα), both of which are stored in the granules of mast cells; IL-15 and thymic stromal lymphopoietin (TSLP), which are secreted by stromal cells.29,30 Another signal that is critical for DCs to acquire the ability to launch T-cell immune responses involves the ligation of the co-stimulatory receptor CD40 (also known as TNFRSF5).31,32 The capacity of DCs to respond to so many stimuli reflect a functional elasticity that can be explained by the large panel of molecular sensors found in these cells. Indeed, DCs not only express multiple pattern-recognition receptors (PRRs) including cell surface C-type lectins, cell surface and endosomal Toll-like receptors (TLRs), intracellular helicases and NOD-like receptors (NLRs), but also a diversified array of cytokine/chemokine receptors.33,34 Of note, most—if not all—adjuvants that are currently employed in vaccine formulations primarily act by triggering the maturation of DCs.

As compared with iDCs, mature DCs (mDCs) exhibit (1) a largely compromised ability to capture antigens, (2) increased exposure of MHC Class II molecules at the cell surface, (3) the expression of chemokine receptors that are required for their migration to lymphoid organs upon antigen uptake (e.g., CCR7), and (4) an increased capacity to secrete cytokines/chemokines.20 In addition, mature DCs are highly efficient at eliciting adaptive immune responses, much more than other antigen-presenting cells (APCs) such as macrophages.35 In this context, different DC subsets appear to regulate not only humoral vs. cellular immunity, but also more refined aspects of the latter.36-38 Thus, while human CD14+ dermal DCs mainly stimulate naïve B cells to differentiate into antibody-producing plasma cells and memory B cells, via an IL-12-dependent mechanism, epidermal Langerhans cells preferentially stimulate CD8+ T-cell responses through the production of IL-15.7,39 At present, it remains unclear to which extent the induction of CD8+ T-cell responses by Langerhans cells is mediated by the direct cross-presentation of antigens on MHC Class I molecules as opposed to the stimulation of CD4+ T-cell helper functions. Of note, it has recently been suggested that Langerhans cells also mediate tolerogenic functions, at least in some settings including allergic contact dermatitis, by directly inhibiting CD8+ T cells and/or by activating a specific subset of Tregs.40 Irrespective of these unresolved issues, it appears that circulating CD141+ DCs (the human homologs of murine CD8α+ DCs) would constitute the DC subset most efficient at cross-presentation.41-44 Gene knockout studies in mice have demonstrated that CD8α+ DCs not only are critical for antigen cross-presentation in vivo, but also promote humoral immunity, perhaps by releasing IL-12.45 In line with this notion, targeting antigens to CD8α+ DCs in vivo via antibodies that specifically recognize their surface marker CLEC9A has been shown to elicit potent cytotoxic T lymphocyte (CTL) and antibody responses, even in the absence of adjuvants.46

One particular subset of DCs is constituted by plasmacytoid DCs (pDCs), which — opposed to their myeloid (or “conventional”) counterparts — have been first identified in humans.1,47,48 pDCs were named after their morphological resemblance to antibody-producing plasma cells and were soon recognized as potent stimulators of Th1 responses, owing to their ability to secrete high quantities of Type I IFN (in both mice and humans) and IL-12 (only in mice).49-51 Actually, both mDCs and pDCs are known to secrete Type I IFN in response to an array of stimuli, but for the latter this array is much larger than for the former, encompassing live and inactivated viruses as well as self-nucleic acids. Most likely, this is due to the fact that — at odds with their myeloid counterparts — pDCs express both TLR7 and TLR9 in the endosomal compartment, providing them with a superior capacity to detect MAMPs and DAMPs.52-54

Given their critical role at the interface between innate and adaptive immune responses, it is not surprising that DCs are involved in the pathophysiology of multiple human diseases involving immunity, including (though perhaps not limited to) infection, chronic inflammation, autoimmunity and allergy.19,55 For instance, the specific depletion of DCs has been experimentally associated with an increased susceptibility to Mycobacterium tuberculosis,56 Toxoplasma gondii,57 herpes simplex virus Type I and II,58 cytomegalovirus,59 and lymphocytic choriomeningitis virus infection.59,60 In addition, several pathogens have devised strategies for avoiding the activation of DCs,61-64 hijacking DC functions toward the establishment of a non-protective Th2 response65,66 or even exploiting DCs for replication.19,67 Along similar lines, the tolerogenic functions of iDCs appears to be compromised in several autoimmune disorders including, but not limited to, psoriasis,68,69 systemic lupus erythematosus (SLE),70 dermatomyositis,71,72 and inflammatory bowel disease,73-75 as well as in allergic conditions, a setting in which TSLP may play a prominent role.76,77 Of note, recent results indicate that pDCs may actively contribute to the pathogenesis of SLE, owing to their capacity to respond to the so-called neutrophil extracellular traps (i.e., complexes containing self DNA and pro-inflammatory molecules that are released by neutrophils in the course of SLE) by secreting large amounts of Type I IFN.78,79

According to the currently accepted model of immunoediting, neoplasms acquire the ability to develop and grow in spite of a proficient immune system in three sequential steps.80,81 Initially, the growth of cancer cells is efficiently controlled, owing to the elicitation of robust tumor-specific immune responses (elimination). As the elimination phase is normally unable to completely eradicate malignant cells, some of them may acquire alterations that either reduce their immunogenicity or increase their resistance to the cytotoxic functions of the immune system (equilibrium). Such cells eventually grow out uncontrolled (escape), leading to clinically manifest cancer.80,81 Often, the equilibrium/escape phases occur along with the establishment of an immunosuppressive local microenvironment that involves, among multiple mechanisms,82,83 the conditioning of tumor-infiltrating DCs toward a tolerogenic phenotype.84,85 Thus, similar to invading pathogens, malignant cells evolve mechanisms for the subversion of DC-mediated responses.

Nevertheless, during the last two decades, DCs have been shown to provide a prominent contribution to the efficacy of multiple chemotherapeutic and immunotherapeutic anticancer regimens.86 Thus, the therapeutic efficacy of conventional chemotherapeutics including, though probably not limited to, anthracyclines (e.g., doxorubicin, mitoxantrone), cyclophosphamide and oxaliplatin, has turned out to rely, at least in part, on the induction of immunogenic cancer cell death,87-91 a functionally distinct type of apoptosis leading to DC-mediated priming of a potent antitumor CTL response.92 Along similar lines, multiple targeted anticancer agents including monoclonal antibodies (e.g., trastuzumab, cetuximab, panitumumab, rituximab)93 as well as receptor tyrosine kinase inhibitors (e.g., imatinib)94 appear to mediate therapeutic effects, at least in part, via off-target immune mechanisms that involve DCs.86

In the same period, a consistent amount of preclinical and clinical results has been gathered indicating that DCs underlie a very promising immunotherapeutic approach to cancer themselves.95 Thus, a large array of cancer vaccination strategies based on DCs have been developed, which can be subdivided into three main categories.20 The first group of DC-based anticancer vaccines encompasses strategies whereby DCs are generated by culturing patient-derived hematopoietic progenitor cells or monocytes with specific cytokine combinations, loaded with tumor-associated antigens (TAAs) ex vivo (by multiple distinct means yet invariably in the presence of an adjuvant, to promote DC maturation), and eventually re-infused into the patient, most often intradermally and in combination with several local courses of an adjuvant.20,30 The most common means for the ex vivo loading of DCs with TAAs include: (1) the co-incubation of DCs with whole tumor cell lysates or with apoptotic tumor cell corpses;96 (2) the co-incubation of DCs with purified TAAs (encompassing both full-length proteins and short peptides); (3) the transfection of DCs with tumor cell-derived mRNA; (4) the genetic manipulation of DCs for the endogenous expression of TAAs; and (5) the fusion of DCs with tumor cells.97-99 As an alternative, autologous DCs are expanded ex vivo (in the absence of TAAs), sometimes genetically engineered for the self-provision of proliferation/activation signals,100 and then re-infused intratumorally, either before or after a therapeutic intervention.101-104 Each of these approaches is associated with specific advantages and drawbacks whose detailed discussion exceeds the scope of this Trial Watch and can be found elsewhere.98,105

Ex vivo-generated DC-based preparations have been tested in cancer patients for more than a decade.30 While objective clinical responses have been recorded only in some settings,106 taken together these studies demonstrate that DC-based vaccines exhibit a good safety profile and can elicit the expansion of circulating TAA-specific CD4+ and CD8+ cells.20,30 Importantly, the clinical success of DCs as an anticancer intervention has been sealed in 2010 with the approval by FDA of a DC-based therapeutic vaccine (sipuleucel-T) for use in patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer.107-109

The second group of DC-based anticancer vaccines comprises strategies whereby TAAs are delivered to DCs in vivo.98,105,110 Such an approach can be achieved by coupling TAAs to monoclonal antibodies or other vectors that specifically recognize DC surface receptors like CLEC9A, DEC205, DC-SIGN, DCIR or globotriaosylceramide (Gb3) but requires the co-delivery of DC maturation signals (as otherwise DCs would drive tolerance).3,111-121 In vivo DC targeting is advantageous in that it does not require the expensive and time-consuming generation of clinical grade DC preparations, but so far has been explored to limited extents, especially in the clinical setting. Another advantage of this approach, at least on theoretical grounds, is that chimeric proteins can be designed allowing for the simultaneous delivery of antigens to DCs and for the provision of specific activation signals (for instance upon the engagement of CLEC7A or CD40).20 This said, further insights into the mechanisms that precisely regulate immune responses elicited by the in vivo delivery of TAAs to DCs are required for this promising strategy to be translated into a clinical reality.20

The third class of DC-based immunotherapeutic interventions against cancer includes approaches based on DC-derived exosomes.122-124 Exosomes are small (30–90 nm in diameter), membrane-surrounded vesicles that are released by a wide range of mammalian cell types, including neoplastic cells and DCs.125-127 Originating from the fusion of multivesicular bodies with the plasma membrane, exosomes have been shown to modulate multiple biological functions, including cell-to-cell communication and membrane dynamics.125-127 DC-derived exosomes are not only highly enriched in MHC Class II molecules (100 fold, as compared with DCs), but also can be produced in conditions that result in the expression of high levels of co-stimulatory molecules including CD40, CD80 and CD86.128 In line with these biological properties, DC-derived exosomes are fully capable of activating adaptive immune responses once loaded with TAAs and inoculated in vivo in suitable animal models.122,129-131

For the development of efficient antitumor vaccines, great efforts have been dedicated at the identification of antigens that would yield to robust, therapeutically beneficial immune responses. This is obviously an important parameter, potentially influencing (though perhaps not entirely dictating) the outcome of DC-based (as well as of other forms of) immunotherapy. Candidates include mutated antigens, which—at least theoretically—can be recognized as non-self by the immune system, as well as wild type self antigens.132,133 The latter have often been selected as they may lead to the development of broadly applicable anticancer vaccines. Still, T-cell clones with a high avidity for common self antigens are likely to be deleted via negative selection, and often memory T cells recognizing these antigens include immunosuppressive Tregs.134,135 Importantly, the use of mutated antigens may circumvent these limitations, yet it requires the identification of antigens on a fully personalized basis, an approach that only now starts to become feasible thanks to the development of efficient RNA sequencing technologies.

Along the lines of our Trial Watch series,136-141 here we will discuss recently completed or ongoing clinical trials that have evaluated/are evaluating DC-based preparations as therapeutic anticancer vaccines.

DCs Loaded Ex Vivo with Tumor Cell Lysates or Apoptotic Bodies

By the late 1990s/early 2000s, the capacity of DCs matured ex vivo in the presence of whole tumor cell lysates or apoptotic tumor cells to elicit therapeutic antitumor immunity in vivo had been firmly established.142-147 Since then, great experimental efforts have been dedicated to the identification of factors that may influence the immunological outcome of this approach.20 Of note, it has been suggested that DCs loaded with apoptotic tumor cells would be superior to DCs pulsed with tumor cell lysates, to DCs fused with tumor cells as well as to DCs transfected with tumor-derived mRNA in eliciting immune responses in vivo.148-151

During the last decade, a wide array of Phase I/II clinical trials has been launched to test the safety and efficacy of this therapeutic strategy in cancer patients. These studies have been performed in a very wide range of settings, encompassing B-cell lymphoma,152 chronic lymphocytic leukemia (CLL),148,153-156 cutaneous T-cell lymphoma (CTCL),157 glioma,158-161 glioblastoma multiforme (GBM),162-165 thyroid carcinoma,166,167 non-small cell lung carcinoma (NSCLC),168-170 breast carcinoma,171,172 mesothelioma,173 hepatocellular carcinoma (HCC),174,175 intrahepatic cholangiocarcinoma,176 melanoma,177-193 pancreatic carcinoma,194 colorectal carcinoma (CRC),195-200 renal cell carcinoma (RCC),171,201-210 prostate cancer,211,212 pediatric malignancies,213-215 and mixed advanced cancers.216-219 Taken together, the results of these studies were very encouraging as they indicated that (1) DCs pulsed ex vivo with tumor cell lysates or with cancer cells succumbing to apoptosis can be administered to patients in the absence of particular toxicity, and that (2) this approach leads to the activation of an immune response in a very large proportion of cases. This said, objective clinical responses were reported in a relatively limited number of studies,152,160,164,165,175,179,180,187,189,191,194,195,198,200,202,209,219,220 perhaps linked to the fact that the Response Evaluation Criteria In Solid Tumors (RECIST) have recently been shown to be inappropriate for assessing the clinical efficacy of immunotherapeutic interventions.20,221,222 In spite of this (perhaps only apparently) moderate rate of clinical success, some studies were able to correlate the development of antitumor immune responses (as assessed by the appearance of delayed Type IV hypersensitivity, DTH) with improved clinical outcomes,164,179,187,219,220 thus maintaining the interest in this immunotherapeutic strategy high.

DCs matured ex vivo in the presence of apoptotic tumor cells are being tested, as a single immunotherapeutic intervention in acute myeloid leukemia (AML) patients (NCT01146262) as well as in subjects affected by brain neoplasms (NCT00893945). In addition, DCs loaded ex vivo with tumor cell lysates (alone or in the presence of the immunostimulatory protein keyhole limpet hemocyanin, KLH) are being employed in B-cell lymphoma and MM patients, as a standalone intervention (NCT00937183); in individuals affected by brain tumors, combined with the TLR3 agonist polyinosinic-polycytidylic acid (polyIC) and/or the TLR7 agonist imiquimod (NCT01171469, NCT01204684); in neuroblastoma and sarcoma patients, combined with IL-4 (NCT00923351); in GBM patients, associated with the standard therapeutic approach involving radiotherapy, surgery and temozolomide (NCT01567202, NCT01213407); in subjects affected by glioma, in combination with cytokine-induced killer (CIK) cells and IL-2 (NCT01235845); in breast carcinoma (NCT01431196), melanoma (NCT01042366), CRC (NCT01348256; NCT01413295) and ovarian cancer (NCT00683241, NCT00703105, NCT01132014) patients, as a single immunotherapeutic intervention; in mesothelioma patients, combined with cyclophosphamide (NCT01241682); in prostate cancer patients, combined with androgen ablation (NCT00970203); in individuals affected by RCC, combined with either CIK cells or with the vascular endothelial growth factor (VEGF)-targeting monoclonal antibody bevacizumab plus an immunostimulatory cocktail including IL-2 and IFNα (NCT00862303, NCT00913913); in patients with tumors of the reproductive tract, together with bevacizumab, cyclophosphamide, fludarabine and anti-CD3/anti-CD8-stimulated autologous T cells (NCT01312376); and in patients with multiple solid tumors, combined with granulocyte macrophage colony-stimulating factor (GM-CSF) plus IFNα (NCT00610389). Two of these trials (NCT01171469, NCT00923351) have been suspended, for unspecified reasons, while all the others are listed as active (source www.clinicaltrials.gov). Intriguingly, two of these trials involve the use of autologous DCs loaded with oxidized tumor cell lysates, a procedure that has been associated with increased immunogenicity in preclinical settings.223

Table 1 reports recent (studies registered at www.clinicaltrials.gov later than 2008, January 1st) clinical trials evaluating, in oncological settings, the safety and efficacy of DCs loaded ex vivo with tumor cell lysates or apoptotic tumor cells.

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Table 1. Clinical trials evaluating DCs loaded ex vivo with tumor cell lysates or apoptotic tumor cells as an immunotherapeutic intervention against cancer.*

DCs Pulsed Ex Vivo with Purified TAAs

The notion that DCs exposed ex vivo to purified/recombinant TAAs (be them full-length proteins or short peptides) can elicit both protective and therapeutic anticancer immune responses in vivo was first demonstrated in 1995, independently, by the laboratories of Michael Lotze and Cornelius Melief.224,225 In the following few years, the therapeutic potential of antigen-pulsed DCs was confirmed in additional tumor models,226,227 the underlying molecular and cellular circuitries begun to the characterized,228-231 and several strategies for increasing the immunogenicity of this approach were devised, encompassing the genetic manipulation of DCs for the emission of immunostimulatory (e.g., IL-12),232 proliferative (e.g., GM-CSF),233 or chemotactic signals (e.g., lymphotactin).234,235 These research threads have never been dismissed since, leading to an ever increasing understanding of the biology that underlie the immunogenicity of antigen-pulsed DCs and to an ever more refined arsenal of protocols for ex vivo antigen loading.20,105,236 As a standalone example, protein transduction (achieved by fusing TAAs to protein transduction domains such as that of HIV-1 Tat) has been developed as a means to increase the accumulation of purified proteins/peptides in the cytosol of DCs, resulting in the preferential processing of antigens by the proteasome and their presentation on MHC Class I molecules.237 Of note, some B-cell neoplasms including follicular, non-Hodgkin's and mantle cell lymphoma as well as multiple myeloma (MM) produce tumor-specific immunoglobulins that, owing to their idiotypic determinants, can be exploited as TAAs.238,239 Although DC-based interventions against such TAAs have been called “anti-idiotypic vaccines,” they are conceptually equivalent to other approaches employing DCs as a means to elicit a tumor-specific immune response, the only difference being the nature and specificity of the TAA.238,239

The results of the first pilot study testing the safety of DCs loaded ex vivo with purified TAAs (in this case, idiotypic determinants) in cancer patients were published in 1996, and were fairly encouraging: all four follicular B-cell lymphoma patients developed measurable antitumor cellular immune responses, and clinical responses were observed in three of them (one complete regression, one partial regression, and one complete resolution of disease, as assessed by the disappearance of disease-specific molecular markers).240 Since then, this approach has been tested in a consistent number of Phase I/II clinical trials that enrolled patients affected by a wide array of neoplasms including chronic myeloid leukemia (CML),241,242 myeloma,243-249 sarcoma,218,250 glioma,251,252 GBM,253-255 breast carcinoma,256-261 NSCLC,262-265 melanoma,179,184,191,193,266-282 HCC,283 pancreatic carcinoma,284,285 gastrointestinal malignancies,286,287 biliary tract cancer,284 CRC,262,264,288-290 RCC,291-293 ovarian carcinoma,218,256,294,295 cervical carcinoma,296,297 prostate cancer,259,298-311 and other advanced malignancies.312 Altogether, these clinical studies demonstrated that the use of DCs loaded ex vivo with purified TAAs is safe and results in the activation of TAA-specific immunity in a large proportion of patients, some of whom also exhibit partial or complete clinical responses.

In spite of these encouraging results and perhaps linked to the lack of appropriate surrogate markers to assess the clinical efficacy of immunotherapy-based clinical trials,221,222 the vast majority of studies investigating the anticancer activity of DCs loaded ex vivo with purified TAAs have not yet reached Phase III (see below), and perhaps never will. One notable exception to this trend is provided by prostate cancer. Indeed, DCs loaded ex vivo with specific TAAs, in particular prostate acid phosphatase (PAP), were soon demonstrated to elicit clinical responses in a consistent fraction of prostate carcinoma patients,298-304 fostering the launch of multiple Phase III clinical trials,107,313,314 including a large, randomized, double-blind, placebo-controlled multicenter study.107 This latter trial unequivocally demonstrated that autologous DCs loaded and activated ex vivo with recombinant PAP fused to GM-CSF (an immunotherapeutic preparation known as sipuleucel-T) are capable of extending the overall survival of patients affected by asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer by approximately 4 mo.107 Shortly after the release of these results, sipuleucel-T was approved by the FDA for use in humans and begun to be commercialized under the label Provenge®, even though a meticulous phenotypic characterization of the cellular component of this product has not been performed to date.109

Recently (studies registered at www.clinicaltrials.gov later than 2008, January 1st), DCs loaded ex vivo with purified TAAs have been (and, often, are still being) tested in AML, neuroblastoma and sarcoma patients (targeted TAAs: MAGE-A1, MAGE-A3, and NY-ESO-1), as a single intervention (NCT00944580), in combination with decitabine (NCT01483274) or associated with decitabine plus imiquimod (NCT01241162); in individuals affected by various hematological malignancies, combined with IL-4 (NCT00923910); in breast carcinoma patients (targeted TAAs: iLRP, HER2 and p53), either as a standalone intervention (NCT00715832, NCT00879489, NCT00923143) or combined with an aromatase inhibitor, IL-2 and thymosin α1 (NCT00935558); in individuals affected by GBM (targeted TAAs: multiple; NCT01280552) and glioma (targeted TAAs: GAA and others; NCT00612001, NCT00766753), as a single immunotherapeutic approach; in melanoma patients (targeted TAAs: gp100, MAGE-A1, MAGE-A3, MART-1, tyrosinase and others, sometimes in combination with viral peptides), as a standalone intervention (NCT00722098, NCT01082198, NCT01189383) or combined with cyclophosphamide (NCT00683670), daclizumab (NCT00847106), or IL-2, non-myeloablative conditioning chemotherapy and transgenic T cells (NCT00910650); in subjects affected by NSCLC (targeted TAA: cyclin B1), as a single therapeutic agent (NCT01398124); in HCC patients (targeted TAA: AFP), as a standalone intervention (NCT01128803); in ovarian cancer patients (targeted TAAs: MUC1, survivin), as a single immune therapeutic intervention (NCT01068509, NCT01456065, NCT01617629); in patients bearing pancreatic cancer (targeted TAAs: multiple, loaded in combination with polyIC or KLH), either as a single agent (NCT00868114, NCT01410968) or combined with an adenoviral vector encoding TNFα and/or radiotherapy (NCT00868114, NCT00843830); and in prostate cancer patients (targeted TAAs: PAP, PSA, TARP, sometimes loaded in combination with KLH), as a standalone anticancer measure (NCT00972309, NCT01171729). All these clinical trials are Phase I/II studies, and the vast majority of them are currently ongoing. A few exceptions are constituted by NCT00935558, which has been withdrawn due to the lack of patients enrolled, NCT00843830, which has been suspended (listed as temporarily closed to accrual), NCT00944580, which has been prematurely terminated (due to unexpectedly low screening results leading to poor accrual) and NCT01171729, which has been completed (though results have not been released yet).

Sipuleucel-T has recently been/is currently being tested, either as a single intervention or combined with hormonotherapy, in eight distinct clinical trials (including seven Phase II and one Phase III studies) enrolling prostate cancer patients (NCT00715078, NCT00715104, NCT00779402, NCT00901342, NCT01338012, NCT01431391, NCT01477749, NCT01487863). These trials aim at assessing the clinical reliability of different protocols for the derivation of sipuleucel-T from autologous DCs as well as the use of sipuleucel-T as a (partially) off-label medication, for instance in patients affected by hormone-sensitive, rather than hormone-refractory, prostate cancer (source www.clinicaltrials.gov).

Table 2 collects recent clinical trials evaluating the safety and efficacy of DCs loaded ex vivo with purified TAAs in cancer patients.

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Table 2. Clinical trials evaluating DCs loaded ex vivo with purified TAAs as an anticancer immunotherapeutic intervention.*

DCs Pulsed with Tumor-Derived mRNA or Engineered for the Expression of TAAs

The interest in using RNA (be it total RNA extracted from bulk tumor cells or the mRNA coding for a specific TAA synthesized in vitro) as a means to load DCs for the development of anticancer vaccines begun to rise in the late 1990s, thanks to the pioneer work of Eli Gilboa and colleagues at the Duke University.315-317 Approximately in the same period, the efficacy of naked DNA-based vaccines (most often consisting in the electroporation-mediated delivery of constructs for the expression of TAAs) turned out to be enormously increased by protocols resulting in the preferential transfection of DCs, in vivo.318-320 Following this discovery, several laboratories worldwide demonstrated that the infusion of DCs engineered ex vivo with (often — but not always — adenoviral)321 vectors for the expression of TAAs elicits superior immune responses, in vivo, as compared with the direct electroporation of DNA-based vaccines, a notion that in a few years was extended to a wide array of different TAAs and tumor models.322-332 Along similar lines, in the 2000–2010 decade, several reports provided unequivocal proof that—upon re-infusion—DCs pulsed ex vivo with tumor-derived RNA are capable of eliciting both protective and therapeutic anticancer immune responses.333-343

During the last decade, RNA-pulsed DCs as well as DCs engineered for the endogenous expression of TAAs have been evaluated as anticancer immunotherapeutics in a few Phase I/II clinical trials. In particular, DCs electroporated with the mRNA coding for full-length Wilms’ tumor 1 (WT1) have been tested in AML patients;344,345 DCs loaded with the mRNA encoding the carcinoembryonic antigen (CEA) have been used in CRC patients289 as well as in patients with advanced CEA-expressing malignancies;346 DCs transduced with the mRNA coding for the human telomerase reverse transcriptase (hTERT) have been tested in a subject bearing pancreatic cancer,347 and in prostate cancer patients;348 the safety and efficacy of DCs transfected with the mRNA encoding the prostate-specific antigen (PSA)349 or with RNA derived from allogeneic prostate cancer cell lines350,351 have been investigated in prostate cancer patients; and DCs pulsed with autologous tumor RNA (alone or combined with KLH) have been tested in patients affected by various brain tumors,352 glioma,353 neuroblastoma,354 melanoma,350,355 CRC,356 and RCC.357 In addition, DCs stably expressing TAAs (most often upon adenoviral transduction) have been tested in patients with advanced (breast, pancreatic and papillary) cancers (expressed TAA: mucin 1),358 small cell lung carcinoma (SCLC, expressed TAA: mucin p53),359,360 and melanoma (expressed TAAs: tyrosinase, melan A and gp100).361,362 Taken together, these studies demonstrated that RNA-loaded as well genetically-modified DCs can be safely administered to cancer patients, leading (in a fraction of cases) to the activation of an antitumor immune response.

Recently (studies registered at www.clinicaltrials.gov later than 2008, January 1st), DCs transduced (most often by electroporation) with RNA have been (and, often, are still being) tested in patients affected by hematological malignancies encompassing acute myeloid leukemia (AML), CML and MM (transduced TAA-encoding RNA: WT1), as a single immunotherapeutic intervention (NCT00834002, NCT00965224); in individuals affected by brain tumors (including GBM) and neuroectodermal tumors (transduced RNAs: CMV p65 or tumor stem cell-derived RNA), either as a single agent (NCT00639639, NCT00846456) or combined with adoptive T-cell transfer (NCT00626483, NCT00693095, NCT01326104), bevacizumab (given as an adjuvant, NCT00890032) or with the tetanus toxoid (NCT00639639); in breast cancer patients (transduced TAA-encoding RNAs: hTERT, p53 and survivin), combined with cyclophosphamide (NCT00978913); in melanoma patients (transduced RNAs: gp100, hTERT, MAGE-3, MART-1, p53, survivin, TRP2, tyrosinase and tumor cell-derived RNA, sometimes in combination with RNAs coding for immunostimulatory proteins including CD40L, CD70 and TLR4), as a standalone intervention (NCT00672542, NCT00929019, NCT00940004, NCT01066390, NCT01278940, NCT01456104, NCT01530698) or in combination with cyclophosphamide (NCT00978913), temozolomide (NCT00961844) or DCs transfected with RNAs encoding immune modulators such as GITRL (NCT01216436); in subjects affected by ovarian cancer (transduced RNAs: hTERT, survivin and tumor cell-derived RNA), as a single agent (NCT01334047, NCT01456065); in prostate cancer patients (transduced RNAs: PAP, PSA, hTERT, survivin and tumor cell-derived RNA), as a standalone intervention (NCT01153113, NCT01197625, NCT01278914) or combined with docetaxel (NCT01446731); in RCC patients (transduced RNAs: tumor cell-derived RNA plus the mRNA encoding CD40L), invariably in combination with the tyrosine kinase inhibition sunitinib (NCT00678119, NCT01482949, NCT01582672); and in patients affected by advanced solid tumors (transduced TAA-encoding RNA: WT1), as a single immunotherapeutic intervention (NCT01291420).

In addition, DCs engineered to stably express p53 as a TAA have been/are being tested in combination with 1-methyl-d-tryptophan (an inhibitor of indoleamine 2,3-dioxygenase, IDO) in breast cancer patients (NCT01302821), combined with chemotherapy, IL-2, granulocyte colony-stimulating factor (G-CSF, filgrastim) and anti-p53 TCR-transduced lymphocytes in patients with progressive or recurrent metastatic cancer (NCT00704938), and in combination with all-trans retinoic acid, paclitaxel, all-trans retinoic acid plus paclitaxel or ex vivo expanded T cells in SCLC (NCT00617409, NCT00618891, NCT00776295). Along similar lines, MUC1-expressing DCs are being investigated as a single immunotherapeutic intervention against prostate cancer (NCT00852007). Most of these studies are currently ongoing, with a few exceptions. These include NCT00704938 and NCT00776295, which have been prematurely terminated (the latter due to low accrual), NCT01153113, which has been withdrawn (due to the status of investigational new drug being withdrawn by FDA), as well as NCT00834002 and NCT01278940, which have been completed. These results of these latter two studies, however, have not yet been released. Of note, exception made for one sipuleucel-T-based study (NCT00779402), NCT01582672 is the sole clinical trial currently assessing the efficacy of DC-based immunotherapy in a Phase III setting (source www.clinicaltrials.gov).

Table 3 collects recent clinical trials testing the safety and efficacy, as anticancer immunotherapeutics, of DCs transfected ex vivo with tumor-derived mRNA or engineered to express TAAs.

Table thumbnail
Table 3. Clinical trials evaluating DCs transfected ex vivo with tumor-derived mRNA or engineered to express TAAs.*

DCs Fused Ex Vivo with Tumor Cells

The first indications that DCs fused to cancer cells would induce therapeutic antitumor responses in vivo date back to the late 1990s/early 2000s.363-366 Such cell hybrids, also known as “dendritomes,” form spontaneously when DCs are co-cultured with both living and apoptotic tumor cells, though at a very low frequency.363 Thus, multiple protocols have been devised to promote the formation of dendritomes, including approaches based on polyethylene glycol, fusogenic viral glycoproteins and electrofusion.367-370 It has been proposed that—up re-infusion—dendritomes exert a lower immunogenic potential than DCs pulsed ex vivo with apoptotic tumor cells,149-151 perhaps owing to comparatively lower expression levels of co-stimulatory surface markers and/or IL-12.371 Of note, dendritomes have been proposed as a means to drive the activation and expansion ex vivo of antitumor T cell clones for adoptive cell transfer approaches.372

During the last decade, Phase I/II clinical trials have investigated the safety and efficacy of dendritomes373 in patients affected by AML,374 MM,375,376 glioma,377 breast carcinoma,378,379 melanoma,380-385 adrenocortical carcinoma,386 RCC,379,387-391 and mixed solid tumors.392,393 Taken together, these clinical studies demonstrated that the administration of dendritomes to cancer patients is safe and associated with the development of DTH responses (indicative of the activation of the immune system) in a very large proportion of cases. In addition, objective clinical benefits (including disease stabilization as well as partial and complete responses) were reported—at least for a fraction of patients—in the vast majority of the studies, with two notable exceptions. In the first one, none of the 11 metastatic melanoma patients treated with dendritomes plus IL-2 developed DTH, pointing to a problem with the vaccination protocol itself.381 The second one was based on a patient cohort way too small for drawing reliable conclusion. Indeed, only two adrenocortical carcinoma patients were treated with dendritomes and, while they did develop immunological responses, no clinical benefits were observed.386

Recently (studies registered at www.clinicaltrials.gov later than 2008, January 1st), dendritomes have been (and, often, are still being) tested in AML patients, in combination with the anti-PD1 monoclonal antibody CT-011 or with GM-CSF (NCT01096602); in B-cell lymphoma and MM patients, as a single immunotherapeutic agent (NCT00937183); in breast carcinoma patients, alone or combined with recombinant IL-12 (NCT00622401); in melanoma patients, as a standalone intervention (NCT00626860, NCT01042366); in non-Hodgkin lymphoma patients, in combination with cryotherapy and a pneumococcal polyvalent vaccine (NCT01239875); in RCC patients, alone or together with CT-011 (NCT00625755, NCT01441765); as well as in subjects affected by neoplasms of the reproductive tract, combined with GM-CSF alone or GM-CSF plus imiquimod (NCT00799110). Only one of these studies is listed by official sources as completed (NCT00625755), yet its results have not been released yet (source www.clinicaltrials.gov).

Table 4 reports recent clinical trials evaluating the safety and efficacy of dendritomes for cancer therapy.

Table thumbnail
Table 4. Clinical trials evaluating dendritomes as an immunotherapeutic intervention in cancer patients.*

Other DC-Based Approaches

In addition to the strategies described above, several other approaches have been undertaken, with variable rates of success, to harness the immunogenic potential of DCs for cancer therapy.30,394 These include, but are not limited to, the intratumoral administration of DCs expanded ex vivo (but not loaded with TAAs), either preceding or ensuing a therapeutic intervention,101-104 the use of DC-based exosomes,124,126 as well as the direct administration of TAAs fused to DC-specific monoclonal antibodies (in vivo DC targeting).111-113,395 We were unable to find in the literature any clinical report on the safety and efficacy of this latter approach for cancer therapy. Conversely, the safety and efficacy of DC-derived exosomes have already been investigated in two Phase I clinical trials, involving advanced melanoma and NSCLC patients.263,396 The results of these studies indicate that DC-derived exosomes loaded with TAAs can be safely administered to cancer patients, yielding—at least in a fraction of cases—immunological and (partial) clinical responses.263,396

Along similar lines, the intratumoral administration of ex vivo expanded DCs has already been tested in a few Phase I/II clinical trials. Obviously, this approach cannot be undertaken in the wide range of tumors for which an intratumoral injection is associated with a high rate of intervention-associated morbidity, though technical advances are expected to resolve this issue, at least in some cases397 Of note, elevated intratumoral amounts of DCs have often, but not always, associated with an improved clinical outcome,398-402 most likely due to the fact that DCs exist in several functionally distinct subsets, which cannot be appropriately discriminated by means of the common markers detected by immunohistochemistry. Indeed, studies in which DCs were quantified based on maturation-specific markers invariably unveiled a positive correlation between infiltration by mDCs and clinical outcome,403-406 with a single exception provided by CRC patients.407 This is paralleled by the fact that high intratumoral levels of Tregs positively (rather than negatively, as in all other cancers)86 affect CRC prognosis,408 and de facto reflects the very peculiar oncogenesis of CRC, which involves a prominent pro-inflammatory component.409

Irrespective of these issues, intratumoral DCs so far have been tested in small cohorts of breast carcinoma,410 melanoma,410,411 hepatoma,412 soft tissue sarcoma,413 resectable pancreatic carcinoma,104 and advanced cancer patients.414 Cumulatively, the results of these studies further confirmed the notion that the administration of DCs is safe and—at least in fraction of patients—can elicit therapeutic immune responses. Recently (studies registered at www.clinicaltrials.gov later than 2008, January 1st), the safety and efficacy of genetically-unmodified DCs have been (and, often, are still being) investigated in several distinct settings and following multiple strategies. These include: (1) allogeneic DCs employed as a single agent in RCC patients (NCT01525017); (2) autologous DCs used alone against AML (NCT00963521), in combination with radiotherapy in soft tissue sarcoma patients (NCT01347034), or with an allogeneic prostate cancer cell vaccine in patients with non-metastatic prostate cancer (NCT00814892); (3) irradiated autologous DCs tested as a single intervention in AML patients (NCT01373515); (4) autologous iDCs used as standalone agent against pancreatic (NCT00795977) and prostate cancer (NCT00753220), or combined with chemotherapy and/or an experimental TLR4 agonist (picibanil) in head and neck cancer (HNC) (NCT01149902) or pancreatic cancer (NCT00795977) patients; and (5) mDCs in combination with lenalidomide for the therapy of MM (NCT00698776). In addition, a few trials are testing autologous DCs that have been genetically engineered for the production of IL-12 or CCL21 as standalone interventions in melanoma (NCT00815607) and NSCLC (NCT00601094, NCT01574222) patients, respectively. With a single exception (NCT00963521), for which—however—results are not yet available, all these clinical studies have not yet been completed. When this Trial Watch was being redacted (July 2012), official sources listed one single Phase I clinical trial what would test in cancer patients the concept of in vivo DC delivery (NCT01522820). Following recent, encouraging preclinical data,395 this study was enrolling patients affected by a wide spectrum of NY-ESO-1-expressing solid tumors for investigating the safety and efficacy of the TAA NY-ESO-1 fused to a monoclonal antibody specific for the DC surface marker DEC-205. In addition, we found only one (Phase II) clinical study that is currently investigating the use of DC-based exosomes against cancer (NCT01159288). In this latter trial, unresectable NSCLC patients responding to induction chemotherapy are allocated to receive or not DC-derived exosomes pulsed with multiple TAAs including, but not limited to, MAGE-A1, MAGE-A3, MART-1 and NY-ESO-1 (source www.clinicaltrials.gov).

Table 5 summarizes recent clinical trials evaluating the safety and efficacy of antigen-naïve DCs, DC-derived exosomes and in vivo DC targeting strategies for cancer therapy.

Table thumbnail
Table 5. Clinical trials evaluating antigen-naïve DCs, DC-derived exosomes and in vivo DC targeting as immunotherapeutic interventions for cancer therapy.*

Concluding Remarks

Following the discovery that—in the presence of appropriate stimulatory signals—DCs are able to elicit robust (and hence potentially therapeutic) antitumor immune responses, multiple strategies have been devised to harness the potential of this functionally heterogeneous immune cell population for cancer therapy. The efficacy of these approaches, encompassing the re-infusion into patients of autologous DCs expanded, (sometimes) genetically modified and loaded with TAAs ex vivo as well as the administration of TAAs fused with monoclonal antibodies allowing for in vivo DC targeting, has been promptly demonstrated in murine tumor models, encouraging the launch of several Phase I/II clinical trials. In the vast majority of these studies, the administration of DCs was found to be safe and—at least in a fraction of patients—to stimulate detectable antitumor responses. Clinical benefits ranging from disease stabilization to complete responses have also been observed in a variable percentage of cases. However, with the notable exception of FDA-approved sipuleucel-T, whose efficacy against asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer has been amply documented in multiple, double-blind, placebo-controlled, multicenter Phase III trials,107,313,314 the clinical development of DC-based anticancer vaccines appears to be challenging, with most approaches failing to enter Phase III testing.

There are several reasons behind the relatively slow development of DC-based immunotherapeutic interventions. First, until recently, the availability of clinical grade TLR agonists (which are required for DC maturation) was limited. This has been partially circumvented by the use of surrogate compounds, such as clinically approved prophylactic vaccines.415,416 Second, a limited fraction (~10%) of TAAs appears to be immunogenic, and, among these, only a few constitute bona fide tumor-rejection antigens (TRAs), i.e., antigens that elicit an immune response resulting in tumor eradication.417 Thus, great efforts will have to be dedicated to the identification of bona fide TRAs, a highly personalized process that involves single cell exome sequencing followed by functional validation assays.418,419 Of note, contrarily to expectations, it seems that TRAs do not preferentially arise from “driver” oncogenic mutations, suggesting that the oncogenic potential of TAAs does not correlate with their immunogenicity.420 Third, DCs administered to patients may not efficiently localize at the tumor site.421 Thus, even though extratumoral DCs may also provide therapeutic benefits, strategies to direct the migration of DCs toward tumor nests are under development. Forth, owing to the elevated heterogeneity (as well as to the hitherto partial characterization) of the DC system, it remains unclear which specific formulation (i.e., which specific route for the loading of TAAs and which specific subset of DCs) has the highest likelihood to result in the activation of therapeutic anticancer immune responses. Recently, great expectations have been generated by the discovery of CD141+ DCs (the human homologs of murine CD8α+ DCs), which would constitute the DC subset most efficient at cross-presentation.41-44 In addition, the potential of pDCs as professional APCs is being re-evaluated.422 Future investigations will clarify if the specific use of CD141+ DCs or pDCs results in improved therapeutic outcomes.

Finally, one major issue that has hampered the development of DC-based interventions is represented by the fact that, until a few years ago, clinical efficacy in immunotherapy-based trials was assessed by the RECIST.423 These criteria, which have been developed to monitor chemotherapy-based clinical studies, have recently been shown to be inappropriate for the assessment of immunomodulatory interventions, as the activation of antitumor responses is slow and initially may even be paralleled by an increased tumor mass (reflecting the infiltration of immune cells).20,221,222 In line with this notion, the administration of a monoclonal antibody targeting the immunosuppressive receptor cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown—in a randomized Phase III clinical trial—to double the survival of Stage IV melanoma patients in the absence of early tumor shrinkage.424 These observations suggest that overall survival might be the sole objective parameter to assess the clinical efficacy of immunotherapeutic interventions. As the evaluation of clinical trials based on overall survival may be excessively long (and hence discourage the development of potentially valuable immunotherapies), there is an urgent need for the identification of surrogate markers of efficacy. While it has been suggested that the clinical outcome of anticancer vaccines might correlate with the expansion of TAA-specific CTLs,220,425-427 several other factors are involved in the elicitation of therapeutically beneficial immune responses. A better understanding of the molecular and cellular mechanisms whereby efficient immunotherapy translates into objective responses will surely lead to the identification of novel biomarkers that predict the clinical efficacy of DC-based interventions.

Acknowledgments

Authors are supported by the Ligue contre le Cancer (équipes labelisées), AXA Chair for Longevity Research, Cancéropôle Ile-de-France, Institut National du Cancer (INCa), Fondation Bettencourt-Schueller, Fondation de France, Fondation pour la Recherche Médicale, Agence National de la Recherche, the European Commission (Apo-Sys, ArtForce, ChemoRes. Death-Train) and the LabEx Immuno-Oncology.

Glossary

Abbreviations:

AML
acute myeloid leukemia
APC
antigen presenting cell
CEA
carcinoembryonic antigen
CIK
cytokine-induced killer, CLL, chronic lymphocytic leukemia
CML
chronic myeloid leukemia
CRC
colorectal carcinoma
CTCL
cutaneous T-cell lymphoma
CTL
cytotoxic T lymphocyte
CTLA4
cytotoxic T-lymphocyte antigen 4
DAMP
damage-associated molecular pattern
DC
dendritic cell
DTH
delayed Type IV hypersensitivity
Gb3
globotriaosylceramide
GBM
glioblastoma multiforme
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte macrophage colony-stimulating factor
HCC
hepatocellular carcinoma
HNC
head and neck cancer
iDC
immature DC
IDO
indoleamine 2,3-dioxygenase
IFN
interferon
IL
interleukin
KLH
keyhole limpet hemocyanin
mDC
myeloid DC
MAMP
microbe-associated molecular pattern
MM
multiple myeloma
NLR
NOD-like receptor
NK
natural killer
NSCLC
non-small cell lung carcinoma
PAP
prostate acid phosphatase
pDC
plasmacytoid DC
polyIC
polyinosinic-polycytidylic acid
PRR
pattern recognition receptor, PSA, prostate-specific antigen
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
SCLC
small cell lung carcinoma
SLE
systemic lupus erythematosus
TAA
tumor-associated antigen
hTERT
human telomerase reverse transcriptase
TLR
Toll-like receptor
TNFα
tumor necrosis factor α
TRA
tumor-rejection antigen
Tregs
CD4+CD25+FOXP3+ regulatory T cells
TSLP
thymic stromal lymphopoietin
VEGF
vascular endothelial growth factor
WT1
Wilms’ tumor 1

References

1. Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med. 1973;137:1142–62. doi: 10.1084/jem.137.5.1142. [PMC free article] [PubMed] [Cross Ref]
2. Banchereau J, Paczesny S, Blanco P, Bennett L, Pascual V, Fay J, et al. Dendritic cells: controllers of the immune system and a new promise for immunotherapy. Ann N Y Acad Sci. 2003;987:180–7. doi: 10.1111/j.1749-6632.2003.tb06047.x. [PubMed] [Cross Ref]
3. Klechevsky E, Flamar AL, Cao Y, Blanck JP, Liu M, O’Bar A, et al. Cross-priming CD8+ T cells by targeting antigens to human dendritic cells through DCIR. Blood. 2010;116:1685–97. doi: 10.1182/blood-2010-01-264960. [PMC free article] [PubMed] [Cross Ref]
4. Banchereau J, Schuler-Thurner B, Palucka AK, Schuler G. Dendritic cells as vectors for therapy. Cell. 2001;106:271–4. doi: 10.1016/S0092-8674(01)00448-2. [PubMed] [Cross Ref]
5. Jego G, Palucka AK, Blanck JP, Chalouni C, Pascual V, Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity. 2003;19:225–34. doi: 10.1016/S1074-7613(03)00208-5. [PubMed] [Cross Ref]
6. Palucka AK, Ueno H, Fay JW, Banchereau J. Taming cancer by inducing immunity via dendritic cells. Immunol Rev. 2007;220:129–50. doi: 10.1111/j.1600-065X.2007.00575.x. [PubMed] [Cross Ref]
7. Ueno H, Klechevsky E, Morita R, Aspord C, Cao T, Matsui T, et al. Dendritic cell subsets in health and disease. Immunol Rev. 2007;219:118–42. doi: 10.1111/j.1600-065X.2007.00551.x. [PubMed] [Cross Ref]
8. Banchereau J, Pulendran B, Steinman R, Palucka K. Will the making of plasmacytoid dendritic cells in vitro help unravel their mysteries? J Exp Med. 2000;192:F39–44. doi: 10.1084/jem.192.12.F39. [PMC free article] [PubMed] [Cross Ref]
9. Berard F, Blanco P, Davoust J, Neidhart-Berard EM, Nouri-Shirazi M, Taquet N, et al. Cross-priming of naive CD8 T cells against melanoma antigens using dendritic cells loaded with killed allogeneic melanoma cells. J Exp Med. 2000;192:1535–44. doi: 10.1084/jem.192.11.1535. [PMC free article] [PubMed] [Cross Ref]
10. Li D, Romain G, Flamar AL, Duluc D, Dullaers M, Li XH, et al. Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells. J Exp Med. 2012;209:109–21. doi: 10.1084/jem.20110399. [PMC free article] [PubMed] [Cross Ref]
11. Jotwani R, Palucka AK, Al-Quotub M, Nouri-Shirazi M, Kim J, Bell D, et al. Mature dendritic cells infiltrate the T cell-rich region of oral mucosa in chronic periodontitis: in situ, in vivo, and in vitro studies. J Immunol. 2001;167:4693–700. [PMC free article] [PubMed]
12. Matsui T, Connolly JE, Michnevitz M, Chaussabel D, Yu CI, Glaser C, et al. CD2 distinguishes two subsets of human plasmacytoid dendritic cells with distinct phenotype and functions. J Immunol. 2009;182:6815–23. doi: 10.4049/jimmunol.0802008. [PMC free article] [PubMed] [Cross Ref]
13. Nouri-Shirazi M, Banchereau J, Bell D, Burkeholder S, Kraus ET, Davoust J, et al. Dendritic cells capture killed tumor cells and present their antigens to elicit tumor-specific immune responses. J Immunol. 2000;165:3797–803. [PubMed]
14. Rolland A, Guyon L, Gill M, Cai YH, Banchereau J, McClain K, et al. Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis. J Immunol. 2005;174:3067–71. [PubMed]
15. Chomarat P, Banchereau J, Davoust J, Palucka AK. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol. 2000;1:510–4. doi: 10.1038/82763. [PubMed] [Cross Ref]
16. Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol. 2005;5:296–306. doi: 10.1038/nri1592. [PubMed] [Cross Ref]
17. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001;294:1540–3. doi: 10.1126/science.1064890. [PubMed] [Cross Ref]
18. Pulendran B, Palucka K, Banchereau J. Sensing pathogens and tuning immune responses. Science. 2001;293:253–6. doi: 10.1126/science.1062060. [PubMed] [Cross Ref]
19. Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449:419–26. doi: 10.1038/nature06175. [PubMed] [Cross Ref]
20. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265–77. doi: 10.1038/nrc3258. [PMC free article] [PubMed] [Cross Ref]
21. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52. doi: 10.1038/32588. [PubMed] [Cross Ref]
22. Trombetta ES, Mellman I. Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol. 2005;23:975–1028. doi: 10.1146/annurev.immunol.22.012703.104538. [PubMed] [Cross Ref]
23. Itano AA, Jenkins MK. Antigen presentation to naive CD4 T cells in the lymph node. Nat Immunol. 2003;4:733–9. doi: 10.1038/ni957. [PubMed] [Cross Ref]
24. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol. 2003;21:685–711. doi: 10.1146/annurev.immunol.21.120601.141040. [PubMed] [Cross Ref]
25. Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev. 2007;87:99–163. doi: 10.1152/physrev.00013.2006. [PubMed] [Cross Ref]
26. Stranges PB, Watson J, Cooper CJ, Choisy-Rossi CM, Stonebraker AC, Beighton RA, et al. Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity. 2007;26:629–41. doi: 10.1016/j.immuni.2007.03.016. [PMC free article] [PubMed] [Cross Ref]
27. Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6:280–6. doi: 10.1038/ni1165. [PubMed] [Cross Ref]
28. Zou T, Caton AJ, Koretzky GA, Kambayashi T. Dendritic cells induce regulatory T cell proliferation through antigen-dependent and -independent interactions. J Immunol. 2010;185:2790–9. doi: 10.4049/jimmunol.0903740. [PubMed] [Cross Ref]
29. Cheng P, Zhou J, Gabrilovich D. Regulation of dendritic cell differentiation and function by Notch and Wnt pathways. Immunol Rev. 2010;234:105–19. doi: 10.1111/j.0105-2896.2009.00871.x. [PubMed] [Cross Ref]
30. Ueno H, Schmitt N, Klechevsky E, Pedroza-Gonzalez A, Matsui T, Zurawski G, et al. Harnessing human dendritic cell subsets for medicine. Immunol Rev. 2010;234:199–212. doi: 10.1111/j.0105-2896.2009.00884.x. [PMC free article] [PubMed] [Cross Ref]
31. Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I, et al. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994;180:1263–72. doi: 10.1084/jem.180.4.1263. [PMC free article] [PubMed] [Cross Ref]
32. Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med. 2004;199:1607–18. doi: 10.1084/jem.20040317. [PMC free article] [PubMed] [Cross Ref]
33. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20. doi: 10.1016/j.cell.2010.01.022. [PubMed] [Cross Ref]
34. Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol. 2006;6:476–83. doi: 10.1038/nri1845. [PubMed] [Cross Ref]
35. Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol. 2012;30:1–22. doi: 10.1146/annurev-immunol-100311-102839. [PubMed] [Cross Ref]
36. Maldonado-López R, De Smedt T, Michel P, Godfroid J, Pajak B, Heirman C, et al. CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med. 1999;189:587–92. doi: 10.1084/jem.189.3.587. [PMC free article] [PubMed] [Cross Ref]
37. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E, et al. Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci U S A. 1999;96:1036–41. doi: 10.1073/pnas.96.3.1036. [PMC free article] [PubMed] [Cross Ref]
38. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, Yamazaki S, et al. Differential antigen processing by dendritic cell subsets in vivo. Science. 2007;315:107–11. doi: 10.1126/science.1136080. [PubMed] [Cross Ref]
39. Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, Thompson-Snipes L, et al. Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity. 2008;29:497–510. doi: 10.1016/j.immuni.2008.07.013. [PMC free article] [PubMed] [Cross Ref]
40. Gomez de Agüero M, Vocanson M, Hacini-Rachinel F, Taillardet M, Sparwasser T, Kissenpfennig A, et al. Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8(+) T cells and activating Foxp3(+) regulatory T cells. J Clin Invest. 2012;122:1700–11. doi: 10.1172/JCI59725. [PMC free article] [PubMed] [Cross Ref]
41. Bachem A, Güttler S, Hartung E, Ebstein F, Schaefer M, Tannert A, et al. Superior antigen cross-presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med. 2010;207:1273–81. doi: 10.1084/jem.20100348. [PMC free article] [PubMed] [Cross Ref]
42. Crozat K, Guiton R, Contreras V, Feuillet V, Dutertre CA, Ventre E, et al. The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207:1283–92. doi: 10.1084/jem.20100223. [PMC free article] [PubMed] [Cross Ref]
43. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, Angel CE, et al. Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med. 2010;207:1247–60. doi: 10.1084/jem.20092140. [PMC free article] [PubMed] [Cross Ref]
44. Poulin LF, Salio M, Griessinger E, Anjos-Afonso F, Craciun L, Chen JL, et al. Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. J Exp Med. 2010;207:1261–71. doi: 10.1084/jem.20092618. [PMC free article] [PubMed] [Cross Ref]
45. Shortman K, Heath WR. The CD8+ dendritic cell subset. Immunol Rev. 2010;234:18–31. doi: 10.1111/j.0105-2896.2009.00870.x. [PubMed] [Cross Ref]
46. Caminschi I, Proietto AI, Ahmet F, Kitsoulis S, Shin Teh J, Lo JC, et al. The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood. 2008;112:3264–73. doi: 10.1182/blood-2008-05-155176. [PMC free article] [PubMed] [Cross Ref]
47. Swiecki M, Colonna M. Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev. 2010;234:142–62. doi: 10.1111/j.0105-2896.2009.00881.x. [PMC free article] [PubMed] [Cross Ref]
48. Reizis B, Colonna M, Trinchieri G, Barrat F, Gilliet M. Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system? Nat Rev Immunol. 2011;11:558–65. doi: 10.1038/nri3027. [PMC free article] [PubMed] [Cross Ref]
49. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, Ho S, et al. The nature of the principal type 1 interferon-producing cells in human blood. Science. 1999;284:1835–7. doi: 10.1126/science.284.5421.1835. [PubMed] [Cross Ref]
50. Cella M, Facchetti F, Lanzavecchia A, Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nat Immunol. 2000;1:305–10. doi: 10.1038/79747. [PubMed] [Cross Ref]
51. Gilliet M, Boonstra A, Paturel C, Antonenko S, Xu XL, Trinchieri G, et al. The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J Exp Med. 2002;195:953–8. doi: 10.1084/jem.20020045. [PMC free article] [PubMed] [Cross Ref]
52. Kadowaki N, Ho S, Antonenko S, Malefyt RW, Kastelein RA, Bazan F, et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med. 2001;194:863–9. doi: 10.1084/jem.194.6.863. [PMC free article] [PubMed] [Cross Ref]
53. Gibson SJ, Lindh JM, Riter TR, Gleason RM, Rogers LM, Fuller AE, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol. 2002;218:74–86. doi: 10.1016/S0008-8749(02)00517-8. [PubMed] [Cross Ref]
54. Kadowaki N, Liu YJ. Natural type I interferon-producing cells as a link between innate and adaptive immunity. Hum Immunol. 2002;63:1126–32. doi: 10.1016/S0198-8859(02)00751-6. [PubMed] [Cross Ref]
55. Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, et al. IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011;365:127–38. doi: 10.1056/NEJMoa1100066. [PMC free article] [PubMed] [Cross Ref]
56. Tian T, Woodworth J, Sköld M, Behar SM. In vivo depletion of CD11c+ cells delays the CD4+ T cell response to Mycobacterium tuberculosis and exacerbates the outcome of infection. J Immunol. 2005;175:3268–72. [PubMed]
57. Liu CH, Fan YT, Dias A, Esper L, Corn RA, Bafica A, et al. Cutting edge: dendritic cells are essential for in vivo IL-12 production and development of resistance against Toxoplasma gondii infection in mice. J Immunol. 2006;177:31–5. [PubMed]
58. Kassim SH, Rajasagi NK, Zhao X, Chervenak R, Jennings SR. In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. J Virol. 2006;80:3985–93. doi: 10.1128/JVI.80.8.3985-3993.2006. [PMC free article] [PubMed] [Cross Ref]
59. Dalod M, Salazar-Mather TP, Malmgaard L, Lewis C, Asselin-Paturel C, Brière F, et al. Interferon alpha/beta and interleukin 12 responses to viral infections: pathways regulating dendritic cell cytokine expression in vivo. J Exp Med. 2002;195:517–28. doi: 10.1084/jem.20011672. [PMC free article] [PubMed] [Cross Ref]
60. Probst HC, van den Broek M. Priming of CTLs by lymphocytic choriomeningitis virus depends on dendritic cells. J Immunol. 2005;174:3920–4. [PubMed]
61. Khader SA, Partida-Sanchez S, Bell G, Jelley-Gibbs DM, Swain S, Pearl JE, et al. Interleukin 12p40 is required for dendritic cell migration and T cell priming after Mycobacterium tuberculosis infection. J Exp Med. 2006;203:1805–15. doi: 10.1084/jem.20052545. [PMC free article] [PubMed] [Cross Ref]
62. Fugier-Vivier I, Servet-Delprat C, Rivailler P, Rissoan MC, Liu YJ, Rabourdin-Combe C. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med. 1997;186:813–23. doi: 10.1084/jem.186.6.813. [PMC free article] [PubMed] [Cross Ref]
63. Jones CA, Fernandez M, Herc K, Bosnjak L, Miranda-Saksena M, Boadle RA, et al. Herpes simplex virus type 2 induces rapid cell death and functional impairment of murine dendritic cells in vitro. J Virol. 2003;77:11139–49. doi: 10.1128/JVI.77.20.11139-11149.2003. [PMC free article] [PubMed] [Cross Ref]
64. Balboa L, Romero MM, Yokobori N, Schierloh P, Geffner L, Basile JI, et al. Mycobacterium tuberculosis impairs dendritic cell response by altering CD1b, DC-SIGN and MR profile. Immunol Cell Biol. 2010;88:716–26. doi: 10.1038/icb.2010.22. [PubMed] [Cross Ref]
65. Lamhamedi-Cherradi SE, Martin RE, Ito T, Kheradmand F, Corry DB, Liu YJ, et al. Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12. J Immunol. 2008;180:6000–9. [PMC free article] [PubMed]
66. Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol. 2007;82:1407–19. doi: 10.1189/jlb.0507268. [PubMed] [Cross Ref]
67. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000;100:587–97. doi: 10.1016/S0092-8674(00)80694-7. [PubMed] [Cross Ref]
68. Lowes MA, Chamian F, Abello MV, Fuentes-Duculan J, Lin SL, Nussbaum R, et al. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD11a) Proc Natl Acad Sci U S A. 2005;102:19057–62. doi: 10.1073/pnas.0509736102. [PMC free article] [PubMed] [Cross Ref]
69. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med. 2005;202:135–43. doi: 10.1084/jem.20050500. [PMC free article] [PubMed] [Cross Ref]
70. Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006;25:383–92. doi: 10.1016/j.immuni.2006.08.010. [PubMed] [Cross Ref]
71. de Padilla CM, Reed AM. Dendritic cells and the immunopathogenesis of idiopathic inflammatory myopathies. Curr Opin Rheumatol. 2008;20:669–74. doi: 10.1097/BOR.0b013e3283157538. [PubMed] [Cross Ref]
72. Howard OM, Dong HF, Yang D, Raben N, Nagaraju K, Rosen A, et al. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med. 2002;196:781–91. doi: 10.1084/jem.20020186. [PMC free article] [PubMed] [Cross Ref]
73. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, et al. Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med. 2006;203:2473–83. doi: 10.1084/jem.20061099. [PMC free article] [PubMed] [Cross Ref]
74. Napolitani G, Rinaldi A, Bertoni F, Sallusto F, Lanzavecchia A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol. 2005;6:769–76. doi: 10.1038/ni1223. [PMC free article] [PubMed] [Cross Ref]
75. Damen GM, van Lierop P, de Ruiter L, Escher JC, Donders R, Samsom JN, et al. Production of IL12p70 and IL23 by monocyte-derived dendritic cells in children with inflammatory bowel disease. Gut. 2008;57:1480. doi: 10.1136/gut.2008.148650. [PubMed] [Cross Ref]
76. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80. [PubMed]
77. Lambrecht BN, Hammad H. Taking our breath away: dendritic cells in the pathogenesis of asthma. Nat Rev Immunol. 2003;3:994–1003. doi: 10.1038/nri1249. [PubMed] [Cross Ref]
78. Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra20. doi: 10.1126/scitranslmed.3001201. [PMC free article] [PubMed] [Cross Ref]
79. Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med. 2011;3:73ra19. doi: 10.1126/scitranslmed.3001180. [PMC free article] [PubMed] [Cross Ref]
80. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6:715–27. doi: 10.1038/nri1936. [PubMed] [Cross Ref]
81. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70. doi: 10.1126/science.1203486. [PubMed] [Cross Ref]
82. Aspord C, Pedroza-Gonzalez A, Gallegos M, Tindle S, Burton EC, Su D, et al. Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development. J Exp Med. 2007;204:1037–47. doi: 10.1084/jem.20061120. [PMC free article] [PubMed] [Cross Ref]
83. Ghiringhelli F, Ménard C, Terme M, Flament C, Taieb J, Chaput N, et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med. 2005;202:1075–85. doi: 10.1084/jem.20051511. [PMC free article] [PubMed] [Cross Ref]
84. Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004;4:941–52. doi: 10.1038/nri1498. [PubMed] [Cross Ref]
85. Vicari AP, Caux C, Trinchieri G. Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol. 2002;12:33–42. doi: 10.1006/scbi.2001.0400. [PubMed] [Cross Ref]
86. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33. doi: 10.1038/nrd3626. [PubMed] [Cross Ref]
87. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13:1050–9. doi: 10.1038/nm1622. [PubMed] [Cross Ref]
88. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005;202:1691–701. doi: 10.1084/jem.20050915. [PMC free article] [PubMed] [Cross Ref]
89. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15:1170–8. doi: 10.1038/nm.2028. [PubMed] [Cross Ref]
90. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61. doi: 10.1038/nm1523. [PubMed] [Cross Ref]
91. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science. 2011;334:1573–7. doi: 10.1126/science.1208347. [PubMed] [Cross Ref]
92. Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353–63. doi: 10.1038/nri2545. [PMC free article] [PubMed] [Cross Ref]
93. Lee SC, Srivastava RM, López-Albaitero A, Ferrone S, Ferris RL. Natural killer (NK): dendritic cell (DC) cross talk induced by therapeutic monoclonal antibody triggers tumor antigen-specific T cell immunity. Immunol Res. 2011;50:248–54. doi: 10.1007/s12026-011-8231-0. [PMC free article] [PubMed] [Cross Ref]
94. Delahaye NF, Rusakiewicz S, Martins I, Ménard C, Roux S, Lyonnet L, et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med. 2011;17:700–7. doi: 10.1038/nm.2366. [PubMed] [Cross Ref]
95. Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science. 2004;305:200–5. doi: 10.1126/science.1100369. [PubMed] [Cross Ref]
96. Hatfield P, Merrick AE, West E, O’Donnell D, Selby P, Vile R, et al. Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy. J Immunother. 2008;31:620–32. doi: 10.1097/CJI.0b013e31818213df. [PMC free article] [PubMed] [Cross Ref]
97. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004;10:475–80. doi: 10.1038/nm1039. [PubMed] [Cross Ref]
98. Gilboa E. DC-based cancer vaccines. J Clin Invest. 2007;117:1195–203. doi: 10.1172/JCI31205. [PMC free article] [PubMed] [Cross Ref]
99. Tyagi RK, Mangal S, Garg N, Sharma PK. RNA-based immunotherapy of cancer: role and therapeutic implications of dendritic cells. Expert Rev Anticancer Ther. 2009;9:97–114. doi: 10.1586/14737140.9.1.97. [PubMed] [Cross Ref]
100. Satoh Y, Esche C, Gambotto A, Shurin GV, Yurkovetsky ZR, Robbins PD, et al. Local administration of IL-12-transfected dendritic cells induces antitumor immune responses to colon adenocarcinoma in the liver in mice. J Exp Ther Oncol. 2002;2:337–49. doi: 10.1046/j.1359-4117.2002.01050.x. [PubMed] [Cross Ref]
101. Nishioka Y, Hirao M, Robbins PD, Lotze MT, Tahara H. Induction of systemic and therapeutic antitumor immunity using intratumoral injection of dendritic cells genetically modified to express interleukin 12. Cancer Res. 1999;59:4035–41. [PubMed]
102. Yang SC, Hillinger S, Riedl K, Zhang L, Zhu L, Huang M, et al. Intratumoral administration of dendritic cells overexpressing CCL21 generates systemic antitumor responses and confers tumor immunity. Clin Cancer Res. 2004;10:2891–901. doi: 10.1158/1078-0432.CCR-03-0380. [PubMed] [Cross Ref]
103. Hu J, Yuan X, Belladonna ML, Ong JM, Wachsmann-Hogiu S, Farkas DL, et al. Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Res. 2006;66:8887–96. doi: 10.1158/0008-5472.CAN-05-3448. [PubMed] [Cross Ref]
104. Endo H, Saito T, Kenjo A, Hoshino M, Terashima M, Sato T, et al. Phase I trial of preoperative intratumoral injection of immature dendritic cells and OK-432 for resectable pancreatic cancer patients. J Hepatobiliary Pancreat Sci 2011. [PubMed]
105. Tacken PJ, de Vries IJ, Torensma R, Figdor CG. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol. 2007;7:790–802. doi: 10.1038/nri2173. [PubMed] [Cross Ref]
106. Palucka K, Ueno H, Roberts L, Fay J, Banchereau J. Dendritic cells: are they clinically relevant? Cancer J. 2010;16:318–24. doi: 10.1097/PPO.0b013e3181eaca83. [PMC free article] [PubMed] [Cross Ref]
107. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. IMPACT Study Investigators Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22. doi: 10.1056/NEJMoa1001294. [PubMed] [Cross Ref]
108. Higano CS, Small EJ, Schellhammer P, Yasothan U, Gubernick S, Kirkpatrick P, et al. Sipuleucel-T. Nat Rev Drug Discov. 2010;9:513–4. doi: 10.1038/nrd3220. [PubMed] [Cross Ref]
109. Cheever MA, Higano CS. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011;17:3520–6. doi: 10.1158/1078-0432.CCR-10-3126. [PubMed] [Cross Ref]
110. Vingert B, Adotevi O, Patin D, Jung S, Shrikant P, Freyburger L, et al. The Shiga toxin B-subunit targets antigen in vivo to dendritic cells and elicits anti-tumor immunity. Eur J Immunol. 2006;36:1124–35. doi: 10.1002/eji.200535443. [PubMed] [Cross Ref]
111. Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H, et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med. 2004;199:815–24. doi: 10.1084/jem.20032220. [PMC free article] [PubMed] [Cross Ref]
112. Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex Class I products and peripheral CD8+ T cell tolerance. J Exp Med. 2002;196:1627–38. doi: 10.1084/jem.20021598. [PMC free article] [PubMed] [Cross Ref]
113. Hawiger D, Inaba K, Dorsett Y, Guo M, Mahnke K, Rivera M, et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med. 2001;194:769–79. doi: 10.1084/jem.194.6.769. [PMC free article] [PubMed] [Cross Ref]
114. Adotevi O, Vingert B, Freyburger L, Shrikant P, Lone YC, Quintin-Colonna F, et al. B subunit of Shiga toxin-based vaccines synergize with alpha-galactosylceramide to break tolerance against self antigen and elicit antiviral immunity. J Immunol. 2007;179:3371–9. [PubMed]
115. Berraondo P, Nouzé C, Préville X, Ladant D, Leclerc C. Eradication of large tumors in mice by a tritherapy targeting the innate, adaptive, and regulatory components of the immune system. Cancer Res. 2007;67:8847–55. doi: 10.1158/0008-5472.CAN-07-0321. [PubMed] [Cross Ref]
116. Tacken PJ, de Vries IJ, Gijzen K, Joosten B, Wu D, Rother RP, et al. Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. Blood. 2005;106:1278–85. doi: 10.1182/blood-2005-01-0318. [PubMed] [Cross Ref]
117. Cruz LJ, Tacken PJ, Pots JM, Torensma R, Buschow SI, Figdor CG. Comparison of antibodies and carbohydrates to target vaccines to human dendritic cells via DC-SIGN. Biomaterials. 2012;33:4229–39. doi: 10.1016/j.biomaterials.2012.02.036. [PubMed] [Cross Ref]
118. Schreibelt G, Klinkenberg LJ, Cruz LJ, Tacken PJ, Tel J, Kreutz M, et al. The C-type lectin receptor CLEC9A mediates antigen uptake and (cross-)presentation by human blood BDCA3+ myeloid dendritic cells. Blood. 2012;119:2284–92. doi: 10.1182/blood-2011-08-373944. [PubMed] [Cross Ref]
119. Tacken PJ, Ginter W, Berod L, Cruz LJ, Joosten B, Sparwasser T, et al. Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation. Blood. 2011;118:4111–9. doi: 10.1182/blood-2011-04-346957. [PubMed] [Cross Ref]
120. Tacken PJ, Ter Huurne M, Torensma R, Figdor CG. Antibodies and carbohydrate ligands binding to C-type lectin DC-SIGN differentially modulate receptor trafficking. Eur J Immunol. 2012 doi: 10.1002/eji.201142258. [PubMed] [Cross Ref]
121. Tacken PJ, Zeelenberg IS, Cruz LJ, van Hout-Kuijer MA, van de Glind G, Fokkink RG, et al. Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity. Blood. 2011;118:6836–44. doi: 10.1182/blood-2011-07-367615. [PubMed] [Cross Ref]
122. Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med. 1998;4:594–600. doi: 10.1038/nm0598-594. [PubMed] [Cross Ref]
123. Théry C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, et al. Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol. 1999;147:599–610. doi: 10.1083/jcb.147.3.599. [PMC free article] [PubMed] [Cross Ref]
124. Viaud S, Théry C, Ploix S, Tursz T, Lapierre V, Lantz O, et al. Dendritic cell-derived exosomes for cancer immunotherapy: what’s next? Cancer Res. 2010;70:1281–5. doi: 10.1158/0008-5472.CAN-09-3276. [PubMed] [Cross Ref]
125. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006;107:102–8. doi: 10.1016/j.imlet.2006.09.005. [PubMed] [Cross Ref]
126. Chaput N, Flament C, Viaud S, Taieb J, Roux S, Spatz A, et al. Dendritic cell derived-exosomes: biology and clinical implementations. J Leukoc Biol. 2006;80:471–8. doi: 10.1189/jlb.0206094. [PubMed] [Cross Ref]
127. Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–79. [PubMed]
128. Viaud S, Ploix S, Lapierre V, Théry C, Commere PH, Tramalloni D, et al. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-γ J Immunother. 2011;34:65–75. doi: 10.1097/CJI.0b013e3181fe535b. [PubMed] [Cross Ref]
129. Wolfers J, Lozier A, Raposo G, Regnault A, Théry C, Masurier C, et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med. 2001;7:297–303. doi: 10.1038/85438. [PubMed] [Cross Ref]
130. Chaput N, Schartz NE, André F, Taïeb J, Novault S, Bonnaventure P, et al. Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. J Immunol. 2004;172:2137–46. [PubMed]
131. André F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol. 2004;172:2126–36. [PubMed]
132. Finn OJ. Cancer vaccines: between the idea and the reality. Nat Rev Immunol. 2003;3:630–41. doi: 10.1038/nri1150. [PubMed] [Cross Ref]
133. Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–15. doi: 10.1056/NEJMra072739. [PubMed] [Cross Ref]
134. Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P. Human T cell responses against melanoma. Annu Rev Immunol. 2006;24:175–208. doi: 10.1146/annurev.immunol.24.021605.090733. [PubMed] [Cross Ref]
135. Parmiani G, De Filippo A, Novellino L, Castelli C. Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol. 2007;178:1975–9. [PubMed]
136. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial Watch: Adoptive cell transfer immunotherapy. Oncoimmunology. 2012;1:306–15. doi: 10.4161/onci.19549. [PMC free article] [PubMed] [Cross Ref]
137. Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. OncoImmunology. 2012;1 doi: 10.4161/onci.20696. In press. [PMC free article] [PubMed] [Cross Ref]
138. Galluzzi L, Vacchelli E, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, et al. Trial Watch: Monoclonal antibodies in cancer therapy. Oncoimmunology. 2012;1:28–37. doi: 10.4161/onci.1.1.17938. [PMC free article] [PubMed] [Cross Ref]
139. Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, et al. Trial Watch: FDA-approved Toll-like receptor agonists for cancer therapy. OncoImmunology. 2012;1 doi: 10.4161/onci.20931. In press. [PMC free article] [PubMed] [Cross Ref]
140. Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L, et al. Trial Watch: Immunostimulatory cytokines. Oncoimmunology. 2012;1:493–506. doi: 10.4161/onci.20459. [PMC free article] [PubMed] [Cross Ref]
141. Vacchelli E, Galluzzi L, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, et al. Trial watch: Chemotherapy with immunogenic cell death inducers. Oncoimmunology. 2012;1:179–88. doi: 10.4161/onci.1.2.19026. [PMC free article] [PubMed] [Cross Ref]
142. Nair SK, Snyder D, Rouse BT, Gilboa E. Regression of tumors in mice vaccinated with professional antigen-presenting cells pulsed with tumor extracts. Int J Cancer. 1997;70:706–15. doi: 10.1002/(SICI)1097-0215(19970317)70:6<706::AID-IJC13>3.0.CO;2-7. [PubMed] [Cross Ref]
143. DeMatos P, Abdel-Wahab Z, Vervaert C, Hester D, Seigler H. Pulsing of dendritic cells with cell lysates from either B16 melanoma or MCA-106 fibrosarcoma yields equally effective vaccines against B16 tumors in mice. J Surg Oncol. 1998;68:79–91. doi: 10.1002/(SICI)1096-9098(199806)68:2<79::AID-JSO3>3.0.CO;2-H. [PubMed] [Cross Ref]
144. DeMatos P, Abdel-Wahab Z, Vervaert C, Seigler HF. Vaccination with dendritic cells inhibits the growth of hepatic metastases in B6 mice. Cell Immunol. 1998;185:65–74. doi: 10.1006/cimm.1998.1277. [PubMed] [Cross Ref]
145. Fields RC, Shimizu K, Mulé JJ. Murine dendritic cells pulsed with whole tumor lysates mediate potent antitumor immune responses in vitro and in vivo. Proc Natl Acad Sci U S A. 1998;95:9482–7. doi: 10.1073/pnas.95.16.9482. [PMC free article] [PubMed] [Cross Ref]
146. Chen Z, Moyana T, Saxena A, Warrington R, Jia Z, Xiang J. Efficient antitumor immunity derived from maturation of dendritic cells that had phagocytosed apoptotic/necrotic tumor cells. Int J Cancer. 2001;93:539–48. doi: 10.1002/ijc.1365. [PubMed] [Cross Ref]
147. Paczesny S, Beranger S, Salzmann JL, Klatzmann D, Colombo BM. Protection of mice against leukemia after vaccination with bone marrow-derived dendritic cells loaded with apoptotic leukemia cells. Cancer Res. 2001;61:2386–9. [PubMed]
148. Kokhaei P, Choudhury A, Mahdian R, Lundin J, Moshfegh A, Osterborg A, et al. Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL. Leukemia. 2004;18:1810–5. doi: 10.1038/sj.leu.2403517. [PubMed] [Cross Ref]
149. Kokhaei P, Rezvany MR, Virving L, Choudhury A, Rabbani H, Osterborg A, et al. Dendritic cells loaded with apoptotic tumour cells induce a stronger T-cell response than dendritic cell-tumour hybrids in B-CLL. Leukemia. 2003;17:894–9. doi: 10.1038/sj.leu.2402913. [PubMed] [Cross Ref]
150. Albert ML, Sauter B, Bhardwaj N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature. 1998;392:86–9. doi: 10.1038/32183. [PubMed] [Cross Ref]
151. Albert ML, Pearce SF, Francisco LM, Sauter B, Roy P, Silverstein RL, et al. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J Exp Med. 1998;188:1359–68. doi: 10.1084/jem.188.7.1359. [PMC free article] [PubMed] [Cross Ref]
152. Zappasodi R, Pupa SM, Ghedini GC, Bongarzone I, Magni M, Cabras AD, et al. Improved clinical outcome in indolent B-cell lymphoma patients vaccinated with autologous tumor cells experiencing immunogenic death. Cancer Res. 2010;70:9062–72. doi: 10.1158/0008-5472.CAN-10-1825. [PubMed] [Cross Ref]
153. Hus I, Roliński J, Tabarkiewicz J, Wojas K, Bojarska-Junak A, Greiner J, et al. Allogeneic dendritic cells pulsed with tumor lysates or apoptotic bodies as immunotherapy for patients with early-stage B-cell chronic lymphocytic leukemia. Leukemia. 2005;19:1621–7. doi: 10.1038/sj.leu.2403860. [PubMed] [Cross Ref]
154. Hus I, Kawiak J, Tabarkiewicz J, Radej S, Hoser G, Bojarska-Junak A, et al. Immunotherapy with irradiated autologous leukemic cells in patients with B-CLL in early stages. Oncol Rep. 2008;20:443–51. [PubMed]
155. Hus I, Schmitt M, Tabarkiewicz J, Radej S, Wojas K, Bojarska-Junak A, et al. Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response. Leukemia. 2008;22:1007–17. doi: 10.1038/leu.2008.29. [PubMed] [Cross Ref]
156. Palma M, Hansson L, Choudhury A, Näsman-Glaser B, Eriksson I, Adamson L, et al. Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol Immunother. 2012;61:865–79. doi: 10.1007/s00262-011-1149-5. [PubMed] [Cross Ref]
157. Maier T, Tun-Kyi A, Tassis A, Jungius KP, Burg G, Dummer R, et al. Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells. Blood. 2003;102:2338–44. doi: 10.1182/blood-2002-08-2455. [PubMed] [Cross Ref]
158. Okada H, Lieberman FS, Walter KA, Lunsford LD, Kondziolka DS, Bejjani GK, et al. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas. J Transl Med. 2007;5:67. doi: 10.1186/1479-5876-5-67. [PMC free article] [PubMed] [Cross Ref]
159. Yamanaka R, Abe T, Yajima N, Tsuchiya N, Homma J, Kobayashi T, et al. Vaccination of recurrent glioma patients with tumour lysate-pulsed dendritic cells elicits immune responses: results of a clinical phase I/II trial. Br J Cancer. 2003;89:1172–9. doi: 10.1038/sj.bjc.6601268. [PMC free article] [PubMed] [Cross Ref]
160. Yamanaka R, Homma J, Yajima N, Tsuchiya N, Sano M, Kobayashi T, et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res. 2005;11:4160–7. doi: 10.1158/1078-0432.CCR-05-0120. [PubMed] [Cross Ref]
161. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res. 2004;64:4973–9. doi: 10.1158/0008-5472.CAN-03-3505. [PubMed] [Cross Ref]
162. Ardon H, Van Gool S, Lopes IS, Maes W, Sciot R, Wilms G, et al. Integration of autologous dendritic cell-based immunotherapy in the primary treatment for patients with newly diagnosed glioblastoma multiforme: a pilot study. J Neurooncol. 2010;99:261–72. doi: 10.1007/s11060-010-0131-y. [PubMed] [Cross Ref]
163. De Vleeschouwer S, Fieuws S, Rutkowski S, Van Calenbergh F, Van Loon J, Goffin J, et al. Postoperative adjuvant dendritic cell-based immunotherapy in patients with relapsed glioblastoma multiforme. Clin Cancer Res. 2008;14:3098–104. doi: 10.1158/1078-0432.CCR-07-4875. [PubMed] [Cross Ref]
164. Fadul CE, Fisher JL, Hampton TH, Lallana EC, Li Z, Gui J, et al. Immune response in patients with newly diagnosed glioblastoma multiforme treated with intranodal autologous tumor lysate-dendritic cell vaccination after radiation chemotherapy. J Immunother. 2011;34:382–9. doi: 10.1097/CJI.0b013e318215e300. [PMC free article] [PubMed] [Cross Ref]
165. Jie X, Hua L, Jiang W, Feng F, Feng G, Hua Z. Clinical application of a dendritic cell vaccine raised against heat-shocked glioblastoma. Cell Biochem Biophys. 2012;62:91–9. doi: 10.1007/s12013-011-9265-6. [PubMed] [Cross Ref]
166. Bachleitner-Hofmann T, Friedl J, Hassler M, Hayden H, Dubsky P, Sachet M, et al. Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma. Oncol Rep. 2009;21:1585–92. doi: 10.3892/or_00000391. [PubMed] [Cross Ref]
167. Kuwabara K, Nishishita T, Morishita M, Oyaizu N, Yamashita S, Kanematsu T, et al. Results of a phase I clinical study using dendritic cell vaccinations for thyroid cancer. Thyroid. 2007;17:53–8. doi: 10.1089/thy.2006.0178. [PubMed] [Cross Ref]
168. Hirschowitz EA, Foody T, Hidalgo GE, Yannelli JR. Immunization of NSCLC patients with antigen-pulsed immature autologous dendritic cells. Lung Cancer. 2007;57:365–72. doi: 10.1016/j.lungcan.2007.04.002. [PMC free article] [PubMed] [Cross Ref]
169. Hirschowitz EA, Foody T, Kryscio R, Dickson L, Sturgill J, Yannelli J. Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol. 2004;22:2808–15. doi: 10.1200/JCO.2004.01.074. [PubMed] [Cross Ref]
170. Um SJ, Choi YJ, Shin HJ, Son CH, Park YS, Roh MS, et al. Phase I study of autologous dendritic cell tumor vaccine in patients with non-small cell lung cancer. Lung Cancer. 2010;70:188–94. doi: 10.1016/j.lungcan.2010.02.006. [PubMed] [Cross Ref]
171. Baek S, Kim CS, Kim SB, Kim YM, Kwon SW, Kim Y, et al. Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial. J Transl Med. 2011;9:178. doi: 10.1186/1479-5876-9-178. [PMC free article] [PubMed] [Cross Ref]
172. Qi CJ, Ning YL, Han YS, Min HY, Ye H, Zhu YL, et al. Autologous dendritic cell vaccine for estrogen receptor (ER)/progestin receptor (PR) double-negative breast cancer. Cancer Immunol Immunother. 2012 doi: 10.1007/s00262-011-1192-2. [PubMed] [Cross Ref]
173. Hegmans JP, Veltman JD, Lambers ME, de Vries IJ, Figdor CG, Hendriks RW, et al. Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am J Respir Crit Care Med. 2010;181:1383–90. doi: 10.1164/rccm.200909-1465OC. [PubMed] [Cross Ref]
174. Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother. 2005;28:496–504. doi: 10.1097/01.cji.0000171291.72039.e2. [PubMed] [Cross Ref]
175. Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49:124–32. doi: 10.1002/hep.22626. [PubMed] [Cross Ref]
176. Shimizu K, Kotera Y, Aruga A, Takeshita N, Takasaki K, Yamamoto M. Clinical utilization of postoperative dendritic cell vaccine plus activated T-cell transfer in patients with intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2012;19:171–8. doi: 10.1007/s00534-011-0437-y. [PubMed] [Cross Ref]
177. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med. 1998;4:328–32. doi: 10.1038/nm0398-328. [PubMed] [Cross Ref]
178. Nagayama H, Sato K, Morishita M, Uchimaru K, Oyaizu N, Inazawa T, et al. Results of a phase I clinical study using autologous tumour lysate-pulsed monocyte-derived mature dendritic cell vaccinations for stage IV malignant melanoma patients combined with low dose interleukin-2. Melanoma Res. 2003;13:521–30. doi: 10.1097/00008390-200310000-00011. [PubMed] [Cross Ref]
179. Hersey P, Menzies SW, Halliday GM, Nguyen T, Farrelly ML, DeSilva C, et al. Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma. Cancer Immunol Immunother. 2004;53:125–34. doi: 10.1007/s00262-003-0429-0. [PubMed] [Cross Ref]
180. Vilella R, Benítez D, Milà J, Lozano M, Vilana R, Pomes J, et al. Pilot study of treatment of biochemotherapy-refractory stage IV melanoma patients with autologous dendritic cells pulsed with a heterologous melanoma cell line lysate. Cancer Immunol Immunother. 2004;53:651–8. doi: 10.1007/s00262-003-0495-3. [PubMed] [Cross Ref]
181. Nakai N, Asai J, Ueda E, Takenaka H, Katoh N, Kishimoto S. Vaccination of Japanese patients with advanced melanoma with peptide, tumor lysate or both peptide and tumor lysate-pulsed mature, monocyte-derived dendritic cells. J Dermatol. 2006;33:462–72. doi: 10.1111/j.1346-8138.2006.00110.x. [PubMed] [Cross Ref]
182. Salcedo M, Bercovici N, Taylor R, Vereecken P, Massicard S, Duriau D, et al. Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate. Cancer Immunol Immunother. 2006;55:819–29. doi: 10.1007/s00262-005-0078-6. [PubMed] [Cross Ref]
183. Bercovici N, Haicheur N, Massicard S, Vernel-Pauillac F, Adotevi O, Landais D, et al. Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients. J Immunother. 2008;31:101–12. doi: 10.1097/CJI.0b013e318159f5ba. [PubMed] [Cross Ref]
184. Hersey P, Halliday GM, Farrelly ML, DeSilva C, Lett M, Menzies SW. Phase I/II study of treatment with matured dendritic cells with or without low dose IL-2 in patients with disseminated melanoma. Cancer Immunol Immunother. 2008;57:1039–51. doi: 10.1007/s00262-007-0435-8. [PubMed] [Cross Ref]
185. Redman BG, Chang AE, Whitfield J, Esper P, Jiang G, Braun T, et al. Phase Ib trial assessing autologous, tumor-pulsed dendritic cells as a vaccine administered with or without IL-2 in patients with metastatic melanoma. J Immunother. 2008;31:591–8. doi: 10.1097/CJI.0b013e31817fd90b. [PMC free article] [PubMed] [Cross Ref]
186. von Euw EM, Barrio MM, Furman D, Levy EM, Bianchini M, Peguillet I, et al. A phase I clinical study of vaccination of melanoma patients with dendritic cells loaded with allogeneic apoptotic/necrotic melanoma cells. Analysis of toxicity and immune response to the vaccine and of IL-10 -1082 promoter genotype as predictor of disease progression. J Transl Med. 2008;6:6. doi: 10.1186/1479-5876-6-6. [PMC free article] [PubMed] [Cross Ref]
187. López MN, Pereda C, Segal G, Muñoz L, Aguilera R, González FE, et al. Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol. 2009;27:945–52. doi: 10.1200/JCO.2008.18.0794. [PubMed] [Cross Ref]
188. Dillman RO, Selvan SR, Schiltz PM, McClay EF, Barth NM, DePriest C, et al. Phase II trial of dendritic cells loaded with antigens from self-renewing, proliferating autologous tumor cells as patient-specific antitumor vaccines in patients with metastatic melanoma: final report. Cancer Biother Radiopharm. 2009;24:311–9. doi: 10.1089/cbr.2008.0599. [PubMed] [Cross Ref]
189. Ribas A, Camacho LH, Lee SM, Hersh EM, Brown CK, Richards JM, et al. Multicenter phase II study of matured dendritic cells pulsed with melanoma cell line lysates in patients with advanced melanoma. J Transl Med. 2010;8:89. doi: 10.1186/1479-5876-8-89. [PMC free article] [PubMed] [Cross Ref]
190. Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, et al. Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis. Clin Dev Immunol 2010; 2010:504979. [PMC free article] [PubMed]
191. Trepiakas R, Berntsen A, Hadrup SR, Bjørn J, Geertsen PF, Straten PT, et al. Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial. Cytotherapy. 2010;12:721–34. doi: 10.3109/14653241003774045. [PubMed] [Cross Ref]
192. Romano E, Rossi M, Ratzinger G, de Cos MA, Chung DJ, Panageas KS, et al. Peptide-loaded Langerhans cells, despite increased IL15 secretion and T-cell activation in vitro, elicit antitumor T-cell responses comparable to peptide-loaded monocyte-derived dendritic cells in vivo. Clin Cancer Res. 2011;17:1984–97. doi: 10.1158/1078-0432.CCR-10-3421. [PMC free article] [PubMed] [Cross Ref]
193. Ellebaek E, Engell-Noerregaard L, Iversen TZ, Froesig TM, Munir S, Hadrup SR, et al. Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer Immunol Immunother. 2012 doi: 10.1007/s00262-012-1242-4. [PubMed] [Cross Ref]
194. Bauer C, Dauer M, Saraj S, Schnurr M, Bauernfeind F, Sterzik A, et al. Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother. 2011;60:1097–107. doi: 10.1007/s00262-011-1023-5. [PubMed] [Cross Ref]
195. Barth RJ, Jr., Fisher DA, Wallace PK, Channon JY, Noelle RJ, Gui J, et al. A randomized trial of ex vivo CD40L activation of a dendritic cell vaccine in colorectal cancer patients: tumor-specific immune responses are associated with improved survival. Clin Cancer Res. 2010;16:5548–56. doi: 10.1158/1078-0432.CCR-10-2138. [PMC free article] [PubMed] [Cross Ref]
196. Burgdorf SK, Claesson MH, Nielsen HJ, Rosenberg J. Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination. Acta Oncol. 2009;48:1157–64. doi: 10.3109/02841860903099964. [PubMed] [Cross Ref]
197. Burgdorf SK, Fischer A, Claesson MH, Kirkin AF, Dzhandzhugazyan KN, Rosenberg J. Vaccination with melanoma lysate-pulsed dendritic cells, of patients with advanced colorectal carcinoma: report from a phase I study. J Exp Clin Cancer Res. 2006;25:201–6. [PubMed]
198. Burgdorf SK, Fischer A, Myschetzky PS, Munksgaard SB, Zocca MB, Claesson MH, et al. Clinical responses in patients with advanced colorectal cancer to a dendritic cell based vaccine. Oncol Rep. 2008;20:1305–11. [PubMed]
199. Tamir A, Basagila E, Kagahzian A, Jiao L, Jensen S, Nicholls J, et al. Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors. Cancer Immunol Immunother. 2007;56:2003–16. doi: 10.1007/s00262-007-0299-y. [PubMed] [Cross Ref]
200. Toh HC, Wang WW, Chia WK, Kvistborg P, Sun L, Teo K, et al. Clinical benefit of allogeneic melanoma cell lysate-pulsed autologous dendritic cell vaccine in MAGE-positive colorectal cancer patients. Clin Cancer Res. 2009;15:7726–36. doi: 10.1158/1078-0432.CCR-09-1537. [PubMed] [Cross Ref]
201. Höltl L, Rieser C, Papesh C, Ramoner R, Herold M, Klocker H, et al. Cellular and humoral immune responses in patients with metastatic renal cell carcinoma after vaccination with antigen pulsed dendritic cells. J Urol. 1999;161:777–82. doi: 10.1016/S0022-5347(01)61767-1. [PubMed] [Cross Ref]
202. Rieser C, Ramoner R, Höltl L, Rogatsch H, Papesh C, Stenzl A, et al. Mature dendritic cells induce T-helper type-1-dominant immune responses in patients with metastatic renal cell carcinoma. Urol Int. 1999;63:151–9. doi: 10.1159/000030438. [PubMed] [Cross Ref]
203. Märten A, Flieger D, Renoth S, Weineck S, Albers P, Compes M, et al. Therapeutic vaccination against metastatic renal cell carcinoma by autologous dendritic cells: preclinical results and outcome of a first clinical phase I/II trial. Cancer Immunol Immunother. 2002;51:637–44. doi: 10.1007/s00262-002-0324-0. [PubMed] [Cross Ref]
204. Gitlitz BJ, Belldegrun AS, Zisman A, Chao DH, Pantuck AJ, Hinkel A, et al. A pilot trial of tumor lysate-loaded dendritic cells for the treatment of metastatic renal cell carcinoma. J Immunother. 2003;26:412–9. doi: 10.1097/00002371-200309000-00004. [PubMed] [Cross Ref]
205. Höltl L, Ramoner R, Zelle-Rieser C, Gander H, Putz T, Papesh C, et al. Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother. 2005;54:663–70. doi: 10.1007/s00262-004-0629-2. [PubMed] [Cross Ref]
206. Matsumoto A, Haraguchi K, Takahashi T, Azuma T, Kanda Y, Tomita K, et al. Immunotherapy against metastatic renal cell carcinoma with mature dendritic cells. Int J Urol. 2007;14:277–83. doi: 10.1111/j.1442-2042.2006.01723.x. [PubMed] [Cross Ref]
207. Berntsen A, Trepiakas R, Wenandy L, Geertsen PF, thor Straten P, Andersen MH, et al. Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial. J Immunother. 2008;31:771–80. doi: 10.1097/CJI.0b013e3181833818. [PubMed] [Cross Ref]
208. Gigante M, Mandic M, Wesa AK, Cavalcanti E, Dambrosio M, Mancini V, et al. Interferon-alpha (IFN-alpha)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients. J Immunother. 2008;31:254–62. doi: 10.1097/CJI.0b013e318167b023. [PubMed] [Cross Ref]
209. Schwaab T, Schwarzer A, Wolf B, Crocenzi TS, Seigne JD, Crosby NA, et al. Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with Aldesleukin (Interleukin 2) and IFN-alpha2a therapy in metastatic renal cell carcinoma patients. Clin Cancer Res. 2009;15:4986–92. doi: 10.1158/1078-0432.CCR-08-3240. [PMC free article] [PubMed] [Cross Ref]
210. Soleimani A, Berntsen A, Svane IM, Pedersen AE. Immune responses in patients with metastatic renal cell carcinoma treated with dendritic cells pulsed with tumor lysate. Scand J Immunol. 2009;70:481–9. doi: 10.1111/j.1365-3083.2009.02322.x. [PubMed] [Cross Ref]
211. Pandha HS, John RJ, Hutchinson J, James N, Whelan M, Corbishley C, et al. Dendritic cell immunotherapy for urological cancers using cryopreserved allogeneic tumour lysate-pulsed cells: a phase I/II study. BJU Int. 2004;94:412–8. doi: 10.1111/j.1464-410X.2004.04922.x. [PubMed] [Cross Ref]
212. Frank MO, Kaufman J, Tian S, Suárez-Fariñas M, Parveen S, Blachère NE, et al. Harnessing naturally occurring tumor immunity: a clinical vaccine trial in prostate cancer. PLoS One. 2010;5 doi: 10.1371/journal.pone.0012367. [PMC free article] [PubMed] [Cross Ref]
213. Ardon H, De Vleeschouwer S, Van Calenbergh F, Claes L, Kramm CM, Rutkowski S, et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr Blood Cancer. 2010;54:519–25. [PubMed]
214. Dohnal AM, Witt V, Hügel H, Holter W, Gadner H, Felzmann T. Phase I study of tumor Ag-loaded IL-12 secreting semi-mature DC for the treatment of pediatric cancer. Cytotherapy. 2007;9:755–70. doi: 10.1080/14653240701589221. [PubMed] [Cross Ref]
215. Geiger JD, Hutchinson RJ, Hohenkirk LF, McKenna EA, Yanik GA, Levine JE, et al. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res. 2001;61:8513–9. [PubMed]
216. Alfaro C, Perez-Gracia JL, Suarez N, Rodriguez J, Fernandez de Sanmamed M, Sangro B, et al. Pilot clinical trial of type 1 dendritic cells loaded with autologous tumor lysates combined with GM-CSF, pegylated IFN, and cyclophosphamide for metastatic cancer patients. J Immunol. 2011;187:6130–42. doi: 10.4049/jimmunol.1102209. [PubMed] [Cross Ref]
217. Chang AE, Redman BG, Whitfield JR, Nickoloff BJ, Braun TM, Lee PP, et al. A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer. Clin Cancer Res. 2002;8:1021–32. [PubMed]
218. Hernando JJ, Park TW, Kübler K, Offergeld R, Schlebusch H, Bauknecht T. Vaccination with autologous tumour antigen-pulsed dendritic cells in advanced gynaecological malignancies: clinical and immunological evaluation of a phase I trial. Cancer Immunol Immunother. 2002;51:45–52. doi: 10.1007/s00262-001-0255-1. [PubMed] [Cross Ref]
219. Ovali E, Dikmen T, Sonmez M, Yilmaz M, Unal A, Dalbasti T, et al. Active immunotherapy for cancer patients using tumor lysate pulsed dendritic cell vaccine: a safety study. J Exp Clin Cancer Res. 2007;26:209–14. [PubMed]
220. de Vries IJ, Bernsen MR, Lesterhuis WJ, Scharenborg NM, Strijk SP, Gerritsen MJ, et al. Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol. 2005;23:5779–87. doi: 10.1200/JCO.2005.06.478. [PubMed] [Cross Ref]
221. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388–97. doi: 10.1093/jnci/djq310. [PMC free article] [PubMed] [Cross Ref]
222. Schlom J, Gulley JL, Arlen PM. Paradigm shifts in cancer vaccine therapy. Exp Biol Med (Maywood) 2008;233:522–34. doi: 10.3181/0708-MR-226. [PubMed] [Cross Ref]
223. Chiang CL, Ledermann JA, Aitkens E, Benjamin E, Katz DR, Chain BM. Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor. Clin Cancer Res. 2008;14:4898–907. doi: 10.1158/1078-0432.CCR-07-4899. [PubMed] [Cross Ref]
224. Mayordomo JI, Zorina T, Storkus WJ, Zitvogel L, Celluzzi C, Falo LD, et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med. 1995;1:1297–302. doi: 10.1038/nm1295-1297. [PubMed] [Cross Ref]
225. Ossevoort MA, Feltkamp MC, van Veen KJ, Melief CJ, Kast WM. Dendritic cells as carriers for a cytotoxic T-lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor. J Immunother Emphasis Tumor Immunol. 1995;18:86–94. doi: 10.1097/00002371-199508000-00002. [PubMed] [Cross Ref]
226. Mayordomo JI, Loftus DJ, Sakamoto H, De Cesare CM, Appasamy PM, Lotze MT, et al. Therapy of murine tumors with p53 wild-type and mutant sequence peptide-based vaccines. J Exp Med. 1996;183:1357–65. doi: 10.1084/jem.183.4.1357. [PMC free article] [PubMed] [Cross Ref]
227. Paglia P, Chiodoni C, Rodolfo M, Colombo MP. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996;183:317–22. doi: 10.1084/jem.183.1.317. [PMC free article] [PubMed] [Cross Ref]
228. Mackey MF, Gunn JR, Maliszewsky C, Kikutani H, Noelle RJ, Barth RJ., Jr. Dendritic cells require maturation via CD40 to generate protective antitumor immunity. J Immunol. 1998;161:2094–8. [PubMed]
229. Zitvogel L, Mayordomo JI, Tjandrawan T, DeLeo AB, Clarke MR, Lotze MT, et al. Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines. J Exp Med. 1996;183:87–97. doi: 10.1084/jem.183.1.87. [PMC free article] [PubMed] [Cross Ref]
230. Mayordomo JI, Zorina T, Storkus WJ, Zitvogel L, Garcia-Prats MD, DeLeo AB, et al. Bone marrow-derived dendritic cells serve as potent adjuvants for peptide-based antitumor vaccines. Stem Cells. 1997;15:94–103. doi: 10.1002/stem.150094. [PubMed] [Cross Ref]
231. Fernandez NC, Lozier A, Flament C, Ricciardi-Castagnoli P, Bellet D, Suter M, et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat Med. 1999;5:405–11. doi: 10.1038/7403. [PubMed] [Cross Ref]
232. Zitvogel L, Couderc B, Mayordomo JI, Robbins PD, Lotze MT, Storkus WJ. IL-12-engineered dendritic cells serve as effective tumor vaccine adjuvants in vivo. Ann N Y Acad Sci. 1996;795:284–93. doi: 10.1111/j.1749-6632.1996.tb52678.x. [PubMed] [Cross Ref]
233. Nakamura M, Iwahashi M, Nakamori M, Ueda K, Matsuura I, Noguchi K, et al. Dendritic cells genetically engineered to simultaneously express endogenous tumor antigen and granulocyte macrophage colony-stimulating factor elicit potent therapeutic antitumor immunity. Clin Cancer Res. 2002;8:2742–9. [PubMed]
234. Zhang W, He L, Yuan Z, Xie Z, Wang J, Hamada H, et al. Enhanced therapeutic efficacy of tumor RNA-pulsed dendritic cells after genetic modification with lymphotactin. Hum Gene Ther. 1999;10:1151–61. doi: 10.1089/10430349950018148. [PubMed] [Cross Ref]
235. Cao X, Zhang W, He L, Xie Z, Ma S, Tao Q, et al. Lymphotactin gene-modified bone marrow dendritic cells act as more potent adjuvants for peptide delivery to induce specific antitumor immunity. J Immunol. 1998;161:6238–44. [PubMed]
236. Palucka K, Ueno H, Banchereau J. Recent developments in cancer vaccines. J Immunol. 2011;186:1325–31. doi: 10.4049/jimmunol.0902539. [PMC free article] [PubMed] [Cross Ref]
237. Batchu RB, Moreno AM, Szmania SM, Bennett G, Spagnoli GC, Ponnazhagan S, et al. Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. Cancer Res. 2005;65:10041–9. doi: 10.1158/0008-5472.CAN-05-1383. [PubMed] [Cross Ref]
238. Houot R, Levy R. Vaccines for lymphomas: idiotype vaccines and beyond. Blood Rev. 2009;23:137–42. doi: 10.1016/j.blre.2008.09.001. [PubMed] [Cross Ref]
239. Rhee F. Idiotype vaccination strategies in myeloma: how to overcome a dysfunctional immune system. Clin Cancer Res. 2007;13:1353–5. doi: 10.1158/1078-0432.CCR-06-2650. [PubMed] [Cross Ref]
240. Hsu FJ, Benike C, Fagnoni F, Liles TM, Czerwinski D, Taidi B, et al. Vaccination of patients with B-cell lymphoma using autologous antigen-pulsed dendritic cells. Nat Med. 1996;2:52–8. doi: 10.1038/nm0196-52. [PubMed] [Cross Ref]
241. Fujii S, Shimizu K, Fujimoto K, Kiyokawa T, Shimomura T, Kinoshita M, et al. Analysis of a chronic myelogenous leukemia patient vaccinated with leukemic dendritic cells following autologous peripheral blood stem cell transplantation. Jpn J Cancer Res. 1999;90:1117–29. doi: 10.1111/j.1349-7006.1999.tb00686.x. [PubMed] [Cross Ref]
242. Takahashi T, Tanaka Y, Nieda M, Azuma T, Chiba S, Juji T, et al. Dendritic cell vaccination for patients with chronic myelogenous leukemia. Leuk Res. 2003;27:795–802. doi: 10.1016/S0145-2126(03)00011-0. [PubMed] [Cross Ref]
243. Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma--a feasibility study. Blood. 1999;93:2411–9. [PubMed]
244. Titzer S, Christensen O, Manzke O, Tesch H, Wolf J, Emmerich B, et al. Vaccination of multiple myeloma patients with idiotype-pulsed dendritic cells: immunological and clinical aspects. Br J Haematol. 2000;108:805–16. doi: 10.1046/j.1365-2141.2000.01958.x. [PubMed] [Cross Ref]
245. Reichardt VL, Milazzo C, Brugger W, Einsele H, Kanz L, Brossart P. Idiotype vaccination of multiple myeloma patients using monocyte-derived dendritic cells. Haematologica. 2003;88:1139–49. [PubMed]
246. Bendandi M, Rodríguez-Calvillo M, Inogés S, López-Díaz de Cerio A, Pérez-Simón JA, Rodríguez-Caballero A, et al. Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation. Leuk Lymphoma. 2006;47:29–37. doi: 10.1080/10428190500272473. [PubMed] [Cross Ref]
247. Curti A, Tosi P, Comoli P, Terragna C, Ferri E, Cellini C, et al. Phase I/II clinical trial of sequential subcutaneous and intravenous delivery of dendritic cell vaccination for refractory multiple myeloma using patient-specific tumour idiotype protein or idiotype (VDJ)-derived class I-restricted peptides. Br J Haematol. 2007;139:415–24. doi: 10.1111/j.1365-2141.2007.06832.x. [PubMed] [Cross Ref]
248. Lacy MQ, Mandrekar S, Dispenzieri A, Hayman S, Kumar S, Buadi F, et al. Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival. Am J Hematol. 2009;84:799–802. doi: 10.1002/ajh.21560. [PMC free article] [PubMed] [Cross Ref]
249. Röllig C, Schmidt C, Bornhäuser M, Ehninger G, Schmitz M, Auffermann-Gretzinger S. Induction of cellular immune responses in patients with stage-I multiple myeloma after vaccination with autologous idiotype-pulsed dendritic cells. J Immunother. 2011;34:100–6. doi: 10.1097/CJI.0b013e3181facf48. [PubMed] [Cross Ref]
250. Dagher R, Long LM, Read EJ, Leitman SF, Carter CS, Tsokos M, et al. Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study. Med Pediatr Oncol. 2002;38:158–64. doi: 10.1002/mpo.1303. [PubMed] [Cross Ref]
251. Yu JS, Wheeler CJ, Zeltzer PM, Ying H, Finger DN, Lee PK, et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Res. 2001;61:842–7. [PubMed]
252. Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with alpha-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011;29:330–6. doi: 10.1200/JCO.2010.30.7744. [PMC free article] [PubMed] [Cross Ref]
253. Liau LM, Black KL, Martin NA, Sykes SN, Bronstein JM, Jouben-Steele L, et al. Treatment of a patient by vaccination with autologous dendritic cells pulsed with allogeneic major histocompatibility complex class I-matched tumor peptides. Case Report. Neurosurg Focus. 2000;9:e8. doi: 10.3171/foc.2000.9.6.9. [PubMed] [Cross Ref]
254. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, Giovannone AJ, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515–25. doi: 10.1158/1078-0432.CCR-05-0464. [PubMed] [Cross Ref]
255. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE, 2nd, Lally-Goss D, et al. An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther. 2009;8:2773–9. doi: 10.1158/1535-7163.MCT-09-0124. [PMC free article] [PubMed] [Cross Ref]
256. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood. 2000;96:3102–8. [PubMed]
257. Dees EC, McKinnon KP, Kuhns JJ, Chwastiak KA, Sparks S, Myers M, et al. Dendritic cells can be rapidly expanded ex vivo and safely administered in patients with metastatic breast cancer. Cancer Immunol Immunother. 2004;53:777–85. doi: 10.1007/s00262-004-0520-1. [PubMed] [Cross Ref]
258. Svane IM, Pedersen AE, Johnsen HE, Nielsen D, Kamby C, Gaarsdal E, et al. Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother. 2004;53:633–41. doi: 10.1007/s00262-003-0493-5. [PubMed] [Cross Ref]
259. Vonderheide RH, Domchek SM, Schultze JL, George DJ, Hoar KM, Chen DY, et al. Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin Cancer Res. 2004;10:828–39. doi: 10.1158/1078-0432.CCR-0620-3. [PubMed] [Cross Ref]
260. Svane IM, Pedersen AE, Johansen JS, Johnsen HE, Nielsen D, Kamby C, et al. Vaccination with p53 peptide-pulsed dendritic cells is associated with disease stabilization in patients with p53 expressing advanced breast cancer; monitoring of serum YKL-40 and IL-6 as response biomarkers. Cancer Immunol Immunother. 2007;56:1485–99. doi: 10.1007/s00262-007-0293-4. [PubMed] [Cross Ref]
261. Svane IM, Pedersen AE, Nikolajsen K, Zocca MB. Alterations in p53-specific T cells and other lymphocyte subsets in breast cancer patients during vaccination with p53-peptide loaded dendritic cells and low-dose interleukin-2. Vaccine. 2008;26:4716–24. doi: 10.1016/j.vaccine.2008.06.085. [PubMed] [Cross Ref]
262. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A. 2001;98:8809–14. doi: 10.1073/pnas.141226398. [PMC free article] [PubMed] [Cross Ref]
263. Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med. 2005;3:9. doi: 10.1186/1479-5876-3-9. [PMC free article] [PubMed] [Cross Ref]
264. Babatz J, Röllig C, Löbel B, Folprecht G, Haack M, Günther H, et al. Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells. Cancer Immunol Immunother. 2006;55:268–76. doi: 10.1007/s00262-005-0021-x. [PubMed] [Cross Ref]
265. Perroud MW, Jr., Honma HN, Barbeiro AS, Gilli SC, Almeida MT, Vassallo J, et al. Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study. J Exp Clin Cancer Res. 2011;30:65. doi: 10.1186/1756-9966-30-65. [PMC free article] [PubMed] [Cross Ref]
266. Banchereau J, Ueno H, Dhodapkar M, Connolly J, Finholt JP, Klechevsky E, et al. Immune and clinical outcomes in patients with stage IV melanoma vaccinated with peptide-pulsed dendritic cells derived from CD34+ progenitors and activated with type I interferon. J Immunother. 2005;28:505–16. doi: 10.1097/01.cji.0000171292.79663.cb. [PubMed] [Cross Ref]
267. Bedrosian I, Mick R, Xu S, Nisenbaum H, Faries M, Zhang P, et al. Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients. J Clin Oncol. 2003;21:3826–35. doi: 10.1200/JCO.2003.04.042. [PubMed] [Cross Ref]
268. Berger TG, Haendle I, Schrama D, Lüftl M, Bauer N, Pedersen LO, et al. Circulation and homing of melanoma-reactive T cells to both cutaneous and visceral metastases after vaccination with monocyte-derived dendritic cells. Int J Cancer. 2004;111:229–37. doi: 10.1002/ijc.20238. [PubMed] [Cross Ref]
269. Carrasco J, Van Pel A, Neyns B, Lethé B, Brasseur F, Renkvist N, et al. Vaccination of a melanoma patient with mature dendritic cells pulsed with MAGE-3 peptides triggers the activity of nonvaccine anti-tumor cells. J Immunol. 2008;180:3585–93. [PubMed]
270. Celis E, Melanoma Study Group of the Mayo Clinic Cancer Center Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma: evidence of systemic immune dysfunction. Cancer. 2007;110:203–14. doi: 10.1002/cncr.22744. [PubMed] [Cross Ref]
271. Di Pucchio T, Pilla L, Capone I, Ferrantini M, Montefiore E, Urbani F, et al. Immunization of stage IV melanoma patients with Melan-A/MART-1 and gp100 peptides plus IFN-alpha results in the activation of specific CD8(+) T cells and monocyte/dendritic cell precursors. Cancer Res. 2006;66:4943–51. doi: 10.1158/0008-5472.CAN-05-3396. [PubMed] [Cross Ref]
272. Fay JW, Palucka AK, Paczesny S, Dhodapkar M, Johnston DA, Burkeholder S, et al. Long-term outcomes in patients with metastatic melanoma vaccinated with melanoma peptide-pulsed CD34(+) progenitor-derived dendritic cells. Cancer Immunol Immunother. 2006;55:1209–18. doi: 10.1007/s00262-005-0106-6. [PubMed] [Cross Ref]
273. Gajewski TF, Fallarino F, Ashikari A, Sherman M. Immunization of HLA-A2+ melanoma patients with MAGE-3 or MelanA peptide-pulsed autologous peripheral blood mononuclear cells plus recombinant human interleukin 12. Clin Cancer Res. 2001;7(Suppl):895s–901s. [PubMed]
274. Laporte M, Trakatelli M, Vereecken P, Blocklet D, Lespagnard M, Petein M, et al. Skin biopsies in DC vaccines for stage III-IV melanoma patients: role of neutrophils? Arch Dermatol Res. 2007;299:483–6. doi: 10.1007/s00403-007-0786-1. [PubMed] [Cross Ref]
275. Lesimple T, Neidhard EM, Vignard V, Lefeuvre C, Adamski H, Labarrière N, et al. Immunologic and clinical effects of injecting mature peptide-loaded dendritic cells by intralymphatic and intranodal routes in metastatic melanoma patients. Clin Cancer Res. 2006;12:7380–8. doi: 10.1158/1078-0432.CCR-06-1879. [PubMed] [Cross Ref]
276. Mackensen A, Herbst B, Chen JL, Köhler G, Noppen C, Herr W, et al. Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34(+) hematopoietic progenitor cells. Int J Cancer. 2000;86:385–92. doi: 10.1002/(SICI)1097-0215(20000501)86:3<385::AID-IJC13>3.0.CO;2-T. [PubMed] [Cross Ref]
277. Panelli MC, Wunderlich J, Jeffries J, Wang E, Mixon A, Rosenberg SA, et al. Phase 1 study in patients with metastatic melanoma of immunization with dendritic cells presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100. J Immunother. 2000;23:487–98. doi: 10.1097/00002371-200007000-00013. [PubMed] [Cross Ref]
278. Peterson AC, Harlin H, Gajewski TF. Immunization with Melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T-cell responses in advanced melanoma. J Clin Oncol. 2003;21:2342–8. doi: 10.1200/JCO.2003.12.144. [PubMed] [Cross Ref]
279. Ribas A, Comin-Anduix B, Chmielowski B, Jalil J, de la Rocha P, McCannel TA, et al. Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin Cancer Res. 2009;15:6267–76. doi: 10.1158/1078-0432.CCR-09-1254. [PMC free article] [PubMed] [Cross Ref]
280. Ribas A, Glaspy JA, Lee Y, Dissette VB, Seja E, Vu HT, et al. Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother. 2004;27:354–67. doi: 10.1097/00002371-200409000-00004. [PubMed] [Cross Ref]
281. Slingluff CL, Jr., Petroni GR, Yamshchikov GV, Barnd DL, Eastham S, Galavotti H, et al. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol. 2003;21:4016–26. doi: 10.1200/JCO.2003.10.005. [PubMed] [Cross Ref]
282. Smithers M, O’Connell K, MacFadyen S, Chambers M, Greenwood K, Boyce A, et al. Clinical response after intradermal immature dendritic cell vaccination in metastatic melanoma is associated with immune response to particulate antigen. Cancer Immunol Immunother. 2003;52:41–52. [PubMed]
283. Sawada Y, Yoshikawa T, Nobuoka D, Shirakawa H, Kuronuma T, Motomura Y, et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: Immunologic evidence and potential for improving overall survival. Clin Cancer Res. 2012;18:3686–96. doi: 10.1158/1078-0432.CCR-11-3044. [PubMed] [Cross Ref]
284. Lepisto AJ, Moser AJ, Zeh H, Lee K, Bartlett D, McKolanis JR, et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 2008;6(B):955–64. [PMC free article] [PubMed]
285. Rong Y, Qin X, Jin D, Lou W, Wu L, Wang D, et al. A phase I pilot trial of MUC1-peptide-pulsed dendritic cells in the treatment of advanced pancreatic cancer. Clin Exp Med. 2011;12:173–80. doi: 10.1007/s10238-011-0159-0. [PubMed] [Cross Ref]
286. Kono K, Takahashi A, Sugai H, Fujii H, Choudhury AR, Kiessling R, et al. Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer. Clin Cancer Res. 2002;8:3394–400. [PubMed]
287. Matsuda K, Tsunoda T, Tanaka H, Umano Y, Tanimura H, Nukaya I, et al. Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells. Cancer Immunol Immunother. 2004;53:609–16. doi: 10.1007/s00262-003-0491-7. [PubMed] [Cross Ref]
288. Kavanagh B, Ko A, Venook A, Margolin K, Zeh H, Lotze M, et al. Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides. J Immunother. 2007;30:762–72. doi: 10.1097/CJI.0b013e318133451c. [PubMed] [Cross Ref]
289. Lesterhuis WJ, De Vries IJ, Schreibelt G, Schuurhuis DH, Aarntzen EH, De Boer A, et al. Immunogenicity of dendritic cells pulsed with CEA peptide or transfected with CEA mRNA for vaccination of colorectal cancer patients. Anticancer Res. 2010;30:5091–7. [PubMed]
290. Sakakibara M, Kanto T, Hayakawa M, Kuroda S, Miyatake H, Itose I, et al. Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. Cancer Immunol Immunother. 2011;60:1565–75. doi: 10.1007/s00262-011-1051-1. [PubMed] [Cross Ref]
291. Bleumer I, Tiemessen DM, Oosterwijk-Wakka JC, Völler MC, De Weijer K, Mulders PF, et al. Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9-peptide-pulsed mature dendritic cells. J Immunother. 2007;30:116–22. doi: 10.1097/01.cji.0000211318.22902.ec. [PubMed] [Cross Ref]
292. Wierecky J, Mueller M, Brossart P. Dendritic cell-based cancer immunotherapy targeting MUC-1. Cancer Immunol Immunother. 2006;55:63–7. doi: 10.1007/s00262-005-0673-6. [PubMed] [Cross Ref]
293. Wierecky J, Müller MR, Wirths S, Halder-Oehler E, Dörfel D, Schmidt SM, et al. Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients. Cancer Res. 2006;66:5910–8. doi: 10.1158/0008-5472.CAN-05-3905. [PubMed] [Cross Ref]
294. Chu CS, Boyer J, Schullery DS, Gimotty PA, Gamerman V, Bender J, et al. Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission. Cancer Immunol Immunother. 2012;61:629–41. doi: 10.1007/s00262-011-1081-8. [PubMed] [Cross Ref]
295. Rahma OE, Ashtar E, Czystowska M, Szajnik ME, Wieckowski E, Bernstein S, et al. A gynecologic oncology group phase II trial of two p53 peptide vaccine approaches: subcutaneous injection and intravenous pulsed dendritic cells in high recurrence risk ovarian cancer patients. Cancer Immunol Immunother. 2012;61:373–84. doi: 10.1007/s00262-011-1100-9. [PMC free article] [PubMed] [Cross Ref]
296. Ferrara A, Nonn M, Sehr P, Schreckenberger C, Pawlita M, Dürst M, et al. Dendritic cell-based tumor vaccine for cervical cancer II: results of a clinical pilot study in 15 individual patients. J Cancer Res Clin Oncol. 2003;129:521–30. doi: 10.1007/s00432-003-0463-5. [PubMed] [Cross Ref]
297. Santin AD, Bellone S, Palmieri M, Zanolini A, Ravaggi A, Siegel ER, et al. Human papillomavirus type 16 and 18 E7-pulsed dendritic cell vaccination of stage IB or IIA cervical cancer patients: a phase I escalating-dose trial. J Virol. 2008;82:1968–79. doi: 10.1128/JVI.02343-07. [PMC free article] [PubMed] [Cross Ref]
298. Murphy GP, Tjoa BA, Simmons SJ, Jarisch J, Bowes VA, Ragde H, et al. Infusion of dendritic cells pulsed with HLA-A2-specific prostate-specific membrane antigen peptides: a phase II prostate cancer vaccine trial involving patients with hormone-refractory metastatic disease. Prostate. 1999;38:73–8. doi: 10.1002/(SICI)1097-0045(19990101)38:1<73::AID-PROS9>3.0.CO;2-V. [PubMed] [Cross Ref]
299. Murphy GP, Tjoa BA, Simmons SJ, Ragde H, Rogers M, Elgamal A, et al. Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate. 1999;39:54–9. doi: 10.1002/(SICI)1097-0045(19990401)39:1<54::AID-PROS9>3.0.CO;2-U. [PubMed] [Cross Ref]
300. Kuratsukuri K, Nishisaka N, Jones RF, Wang CY, Haas GP. Clinical trials of immunotherapy for advanced prostate cancer. Urol Oncol. 2000;5:265–73. doi: 10.1016/S1078-1439(00)00086-7. [PubMed] [Cross Ref]
301. Small EJ, Fratesi P, Reese DM, Strang G, Laus R, Peshwa MV, et al. Immunotherapy of hormone-refractory prostate cancer with antigen-loaded dendritic cells. J Clin Oncol. 2000;18:3894–903. [PubMed]
302. Fong L, Brockstedt D, Benike C, Breen JK, Strang G, Ruegg CL, et al. Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy. J Immunol. 2001;167:7150–6. [PubMed]
303. Fong L, Brockstedt D, Benike C, Wu L, Engleman EG. Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol. 2001;166:4254–9. [PubMed]
304. Valone FH, Small E, MacKenzie M, Burch P, Lacy M, Peshwa MV, et al. Dendritic cell-based treatment of cancer: closing in on a cellular therapy. Cancer J. 2001;7(Suppl 2):S53–61. [PubMed]
305. Barrou B, Benoît G, Ouldkaci M, Cussenot O, Salcedo M, Agrawal S, et al. Vaccination of prostatectomized prostate cancer patients in biochemical relapse, with autologous dendritic cells pulsed with recombinant human PSA. Cancer Immunol Immunother. 2004;53:453–60. doi: 10.1007/s00262-003-0451-2. [PubMed] [Cross Ref]
306. Fuessel S, Meye A, Schmitz M, Zastrow S, Linné C, Richter K, et al. Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial. Prostate. 2006;66:811–21. doi: 10.1002/pros.20404. [PubMed] [Cross Ref]
307. Hildenbrand B, Sauer B, Kalis O, Stoll C, Freudenberg MA, Niedermann G, et al. Immunotherapy of patients with hormone-refractory prostate carcinoma pre-treated with interferon-gamma and vaccinated with autologous PSA-peptide loaded dendritic cells--a pilot study. Prostate. 2007;67:500–8. doi: 10.1002/pros.20539. [PubMed] [Cross Ref]
308. Perambakam S, Hallmeyer S, Reddy S, Mahmud N, Bressler L, DeChristopher P, et al. Induction of specific T cell immunity in patients with prostate cancer by vaccination with PSA146-154 peptide. Cancer Immunol Immunother. 2006;55:1033–42. doi: 10.1007/s00262-005-0090-x. [PubMed] [Cross Ref]
309. Simmons SJ, Tjoa BA, Rogers M, Elgamal A, Kenny GM, Ragde H, et al. GM-CSF as a systemic adjuvant in a phase II prostate cancer vaccine trial. Prostate. 1999;39:291–7. doi: 10.1002/(SICI)1097-0045(19990601)39:4<291::AID-PROS10>3.0.CO;2-9. [PubMed] [Cross Ref]
310. Thomas-Kaskel AK, Zeiser R, Jochim R, Robbel C, Schultze-Seemann W, Waller CF, et al. Vaccination of advanced prostate cancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTH responses that correlate with superior overall survival. Int J Cancer. 2006;119:2428–34. doi: 10.1002/ijc.22097. [PubMed] [Cross Ref]
311. Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, von Moos R, Böhme C, Schmid HP, et al. Dendritic cell-based multi-epitope immunotherapy of hormone-refractory prostate carcinoma. Cancer Immunol Immunother. 2006;55:1524–33. doi: 10.1007/s00262-006-0157-3. [PubMed] [Cross Ref]
312. Loveland BE, Zhao A, White S, Gan H, Hamilton K, Xing PX, et al. Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma. Clin Cancer Res. 2006;12:869–77. doi: 10.1158/1078-0432.CCR-05-1574. [PubMed] [Cross Ref]
313. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089–94. doi: 10.1200/JCO.2005.04.5252. [PubMed] [Cross Ref]
314. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115:3670–9. doi: 10.1002/cncr.24429. [PubMed] [Cross Ref]
315. Boczkowski D, Nair SK, Snyder D, Gilboa E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med. 1996;184:465–72. doi: 10.1084/jem.184.2.465. [PMC free article] [PubMed] [Cross Ref]
316. Ashley DM, Faiola B, Nair S, Hale LP, Bigner DD, Gilboa E. Bone marrow-generated dendritic cells pulsed with tumor extracts or tumor RNA induce antitumor immunity against central nervous system tumors. J Exp Med. 1997;186:1177–82. doi: 10.1084/jem.186.7.1177. [PMC free article] [PubMed] [Cross Ref]
317. Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E. Induction of tumor immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumor cells. Cancer Res. 2000;60:1028–34. [PubMed]
318. Condon C, Watkins SC, Celluzzi CM, Thompson K, Falo LD., Jr. DNA-based immunization by in vivo transfection of dendritic cells. Nat Med. 1996;2:1122–8. doi: 10.1038/nm1096-1122. [PubMed] [Cross Ref]
319. Chattergoon MA, Robinson TM, Boyer JD, Weiner DB. Specific immune induction following DNA-based immunization through in vivo transfection and activation of macrophages/antigen-presenting cells. J Immunol. 1998;160:5707–18. [PubMed]
320. Porgador A, Irvine KR, Iwasaki A, Barber BH, Restifo NP, Germain RN. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J Exp Med. 1998;188:1075–82. doi: 10.1084/jem.188.6.1075. [PMC free article] [PubMed] [Cross Ref]
321. Irvine AS, Trinder PK, Laughton DL, Ketteringham H, McDermott RH, Reid SC, et al. Efficient nonviral transfection of dendritic cells and their use for in vivo immunization. Nat Biotechnol. 2000;18:1273–8. doi: 10.1038/82383. [PubMed] [Cross Ref]
322. Manickan E, Kanangat S, Rouse RJ, Yu Z, Rouse BT. Enhancement of immune response to naked DNA vaccine by immunization with transfected dendritic cells. J Leukoc Biol. 1997;61:125–32. [PubMed]
323. Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, et al. Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity. J Exp Med. 1997;186:1247–56. doi: 10.1084/jem.186.8.1247. [PMC free article] [PubMed] [Cross Ref]
324. Tüting T, DeLeo AB, Lotze MT, Storkus WJ. Genetically modified bone marrow-derived dendritic cells expressing tumor-associated viral or “self” antigens induce antitumor immunity in vivo. Eur J Immunol. 1997;27:2702–7. doi: 10.1002/eji.1830271033. [PubMed] [Cross Ref]
325. Wan Y, Bramson J, Carter R, Graham F, Gauldie J. Dendritic cells transduced with an adenoviral vector encoding a model tumor-associated antigen for tumor vaccination. Hum Gene Ther. 1997;8:1355–63. doi: 10.1089/hum.1997.8.11-1355. [PubMed] [Cross Ref]
326. McArthur JG, Mulligan RC. Induction of protective anti-tumor immunity by gene-modified dendritic cells. J Immunother. 1998;21:41–7. doi: 10.1097/00002371-199801000-00005. [PubMed] [Cross Ref]
327. Ishida T, Chada S, Stipanov M, Nadaf S, Ciernik FI, Gabrilovich DI, et al. Dendritic cells transduced with wild-type p53 gene elicit potent anti-tumour immune responses. Clin Exp Immunol. 1999;117:244–51. doi: 10.1046/j.1365-2249.1999.00913.x. [PMC free article] [PubMed] [Cross Ref]
328. Tüting T, Steitz J, Brück J, Gambotto A, Steinbrink K, DeLeo AB, et al. Dendritic cell-based genetic immunization in mice with a recombinant adenovirus encoding murine TRP2 induces effective anti-melanoma immunity. J Gene Med. 1999;1:400–6. doi: 10.1002/(SICI)1521-2254(199911/12)1:6<400::AID-JGM68>3.0.CO;2-D. [PubMed] [Cross Ref]
329. Wan Y, Emtage P, Zhu Q, Foley R, Pilon A, Roberts B, et al. Enhanced immune response to the melanoma antigen gp100 using recombinant adenovirus-transduced dendritic cells. Cell Immunol. 1999;198:131–8. doi: 10.1006/cimm.1999.1585. [PubMed] [Cross Ref]
330. Klein C, Bueler H, Mulligan RC. Comparative analysis of genetically modified dendritic cells and tumor cells as therapeutic cancer vaccines. J Exp Med. 2000;191:1699–708. doi: 10.1084/jem.191.10.1699. [PMC free article] [PubMed] [Cross Ref]
331. Ribas A, Butterfield LH, Hu B, Dissette VB, Chen AY, Koh A, et al. Generation of T-cell immunity to a murine melanoma using MART-1-engineered dendritic cells. J Immunother. 2000;23:59–66. doi: 10.1097/00002371-200001000-00008. [PubMed] [Cross Ref]
332. Okada N, Saito T, Masunaga Y, Tsukada Y, Nakagawa S, Mizuguchi H, et al. Efficient antigen gene transduction using Arg-Gly-Asp fiber-mutant adenovirus vectors can potentiate antitumor vaccine efficacy and maturation of murine dendritic cells. Cancer Res. 2001;61:7913–9. [PubMed]
333. Koido S, Kashiwaba M, Chen D, Gendler S, Kufe D, Gong J. Induction of antitumor immunity by vaccination of dendritic cells transfected with MUC1 RNA. J Immunol. 2000;165:5713–9. [PubMed]
334. Nair SK, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski JS, et al. Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med. 2000;6:1011–7. doi: 10.1038/79519. [PubMed] [Cross Ref]
335. Yamanaka R, Zullo SA, Tanaka R, Blaese M, Xanthopoulos KG. Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki forest virus-mediated complementary DNA. J Neurosurg. 2001;94:474–81. doi: 10.3171/jns.2001.94.3.0474. [PubMed] [Cross Ref]
336. Insug O, Ku G, Ertl HC, Blaszczyk-Thurin M. A dendritic cell vaccine induces protective immunity to intracranial growth of glioma. Anticancer Res. 2002;22(2A):613–21. [PubMed]
337. Van Meirvenne S, Straetman L, Heirman C, Dullaers M, De Greef C, Van Tendeloo V, et al. Efficient genetic modification of murine dendritic cells by electroporation with mRNA. Cancer Gene Ther. 2002;9:787–97. doi: 10.1038/sj.cgt.7700499. [PubMed] [Cross Ref]
338. Li M, You S, Ge W, Ma S, Ma N, Zhao C. Induction of T-cell immunity against leukemia by dendritic cells pulsed with total RNA isolated from leukemia cells. Chin Med J (Engl) 2003;116:1655–61. [PubMed]
339. Minami T, Nakanishi Y, Izumi M, Harada T, Hara N. Enhancement of antigen-presenting capacity and antitumor immunity of dendritic cells pulsed with autologous tumor-derived RNA in mice. J Immunother. 2003;26:420–31. doi: 10.1097/00002371-200309000-00005. [PubMed] [Cross Ref]
340. Schmidt T, Ziske C, Märten A, Endres S, Tiemann K, Schmitz V, et al. Intratumoral immunization with tumor RNA-pulsed dendritic cells confers antitumor immunity in a C57BL/6 pancreatic murine tumor model. Cancer Res. 2003;63:8962–7. [PubMed]
341. Jung CW, Kwon JH, Seol JG, Park WH, Hyun JM, Kim ES, et al. Induction of cytotoxic T lymphocytes by dendritic cells pulsed with murine leukemic cell RNA. Am J Hematol. 2004;75:121–7. doi: 10.1002/ajh.10471. [PubMed] [Cross Ref]
342. Liu BY, Chen XH, Gu QL, Li JF, Yin HR, Zhu ZG, et al. Antitumor effects of vaccine consisting of dendritic cells pulsed with tumor RNA from gastric cancer. World J Gastroenterol. 2004;10:630–3. [PubMed]
343. Zeis M, Siegel S, Wagner A, Schmitz M, Marget M, Kühl-Burmeister R, et al. Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells. J Immunol. 2003;170:5391–7. [PubMed]
344. Van Driessche A, Van de Velde AL, Nijs G, Braeckman T, Stein B, De Vries JM, et al. Clinical-grade manufacturing of autologous mature mRNA-electroporated dendritic cells and safety testing in acute myeloid leukemia patients in a phase I dose-escalation clinical trial. Cytotherapy. 2009;11:653–68. doi: 10.1080/14653240902960411. [PubMed] [Cross Ref]
345. Van Tendeloo VF, Van de Velde A, Van Driessche A, Cools N, Anguille S, Ladell K, et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci U S A. 2010;107:13824–9. doi: 10.1073/pnas.1008051107. [PMC free article] [PubMed] [Cross Ref]
346. Morse MA, Nair SK, Mosca PJ, Hobeika AC, Clay TM, Deng Y, et al. Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest. 2003;21:341–9. doi: 10.1081/CNV-120018224. [PubMed] [Cross Ref]
347. Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, et al. hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother. 2011;60:809–18. doi: 10.1007/s00262-011-0991-9. [PMC free article] [PubMed] [Cross Ref]
348. Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D, et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol. 2005;174:3798–807. [PubMed]
349. Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, et al. Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumors. J Clin Invest. 2002;109:409–17. [PMC free article] [PubMed]
350. Kyte JA, Gaudernack G. Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells. Cancer Immunol Immunother. 2006;55:1432–42. doi: 10.1007/s00262-006-0161-7. [PubMed] [Cross Ref]
351. Mu LJ, Kyte JA, Kvalheim G, Aamdal S, Dueland S, Hauser M, et al. Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients. Br J Cancer. 2005;93:749–56. doi: 10.1038/sj.bjc.6602761. [PMC free article] [PubMed] [Cross Ref]
352. Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, Maixner W, et al. Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children and young adults with brain cancer. Neuro Oncol. 2004;6:236–46. doi: 10.1215/S1152851703000668. [PMC free article] [PubMed] [Cross Ref]
353. Kobayashi T, Yamanaka R, Homma J, Tsuchiya N, Yajima N, Yoshida S, et al. Tumor mRNA-loaded dendritic cells elicit tumor-specific CD8(+) cytotoxic T cells in patients with malignant glioma. Cancer Immunol Immunother. 2003;52:632–7. doi: 10.1007/s00262-003-0408-5. [PubMed] [Cross Ref]
354. Caruso DA, Orme LM, Amor GM, Neale AM, Radcliff FJ, Downie P, et al. Results of a Phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 neuroblastoma. Cancer. 2005;103:1280–91. doi: 10.1002/cncr.20911. [PubMed] [Cross Ref]
355. Kyte JA, Mu L, Aamdal S, Kvalheim G, Dueland S, Hauser M, et al. Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther. 2006;13:905–18. doi: 10.1038/sj.cgt.7700961. [PubMed] [Cross Ref]
356. Rains N, Cannan RJ, Chen W, Stubbs RS. Development of a dendritic cell (DC)-based vaccine for patients with advanced colorectal cancer. Hepatogastroenterology. 2001;48:347–51. [PubMed]
357. Su Z, Dannull J, Heiser A, Yancey D, Pruitt S, Madden J, et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 2003;63:2127–33. [PubMed]
358. Pecher G, Häring A, Kaiser L, Thiel E. Mucin gene (MUC1) transfected dendritic cells as vaccine: results of a phase I/II clinical trial. Cancer Immunol Immunother. 2002;51:669–73. doi: 10.1007/s00262-002-0317-z. [PubMed] [Cross Ref]
359. Antonia SJ, Mirza N, Fricke I, Chiappori A, Thompson P, Williams N, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res. 2006;12:878–87. doi: 10.1158/1078-0432.CCR-05-2013. [PubMed] [Cross Ref]
360. Chiappori AA, Soliman H, Janssen WE, Antonia SJ, Gabrilovich DI. INGN-225: a dendritic cell-based p53 vaccine (Ad.p53-DC) in small cell lung cancer: observed association between immune response and enhanced chemotherapy effect. Expert Opin Biol Ther. 2010;10:983–91. doi: 10.1517/14712598.2010.484801. [PMC free article] [PubMed] [Cross Ref]
361. Di Nicola M, Carlo-Stella C, Mortarini R, Baldassari P, Guidetti A, Gallino GF, et al. Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic melanoma. Clin Cancer Res. 2004;10:5381–90. doi: 10.1158/1078-0432.CCR-04-0602. [PubMed] [Cross Ref]
362. Steele JC, Rao A, Marsden JR, Armstrong CJ, Berhane S, Billingham LJ, et al. Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma. Gene Ther. 2011;18:584–93. doi: 10.1038/gt.2011.1. [PubMed] [Cross Ref]
363. Celluzzi CM, Falo LD., Jr. Physical interaction between dendritic cells and tumor cells results in an immunogen that induces protective and therapeutic tumor rejection. J Immunol. 1998;160:3081–5. [PubMed]
364. Wang J, Saffold S, Cao X, Krauss J, Chen W. Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines. J Immunol. 1998;161:5516–24. [PubMed]
365. Tanaka H, Shimizu K, Hayashi T, Shu S. Therapeutic immune response induced by electrofusion of dendritic and tumor cells. Cell Immunol. 2002;220:1–12. doi: 10.1016/S0008-8749(03)00009-1. [PubMed] [Cross Ref]
366. Orentas RJ, Schauer D, Bin Q, Johnson BD. Electrofusion of a weakly immunogenic neuroblastoma with dendritic cells produces a tumor vaccine. Cell Immunol. 2001;213:4–13. doi: 10.1006/cimm.2001.1864. [PubMed] [Cross Ref]
367. Kjaergaard J, Shimizu K, Shu S. Electrofusion of syngeneic dendritic cells and tumor generates potent therapeutic vaccine. Cell Immunol. 2003;225:65–74. doi: 10.1016/j.cellimm.2003.09.005. [PubMed] [Cross Ref]
368. Sukhorukov VL, Reuss R, Endter JM, Fehrmann S, Katsen-Globa A, Gessner P, et al. A biophysical approach to the optimisation of dendritic-tumour cell electrofusion. Biochem Biophys Res Commun. 2006;346:829–39. doi: 10.1016/j.bbrc.2006.05.193. [PubMed] [Cross Ref]
369. Cathelin D, Nicolas A, Bouchot A, Fraszczak J, Labbé J, Bonnotte B. Dendritic cell-tumor cell hybrids and immunotherapy: what’s next? Cytotherapy. 2011;13:774–85. doi: 10.3109/14653249.2011.553593. [PubMed] [Cross Ref]
370. Errington F, Jones J, Merrick A, Bateman A, Harrington K, Gough M, et al. Fusogenic membrane glycoprotein-mediated tumour cell fusion activates human dendritic cells for enhanced IL-12 production and T-cell priming. Gene Ther. 2006;13:138–49. doi: 10.1038/sj.gt.3302609. [PubMed] [Cross Ref]
371. Vasir B, Wu Z, Crawford K, Rosenblatt J, Zarwan C, Bissonnette A, et al. Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells. J Immunol. 2008;181:808–21. [PMC free article] [PubMed]
372. Rosenblatt J, Wu Z, Vasir B, Zarwan C, Stone R, Mills H, et al. Generation of tumor-specific T lymphocytes using dendritic cell/tumor fusions and anti-CD3/CD28. J Immunother. 2010;33:155–66. doi: 10.1097/CJI.0b013e3181bed253. [PMC free article] [PubMed] [Cross Ref]
373. Avigan D, Rosenblatt J, Kufe D. Dendritic/tumor fusion cells as cancer vaccines. Semin Oncol. 2012;39:287–95. doi: 10.1053/j.seminoncol.2012.02.003. [PubMed] [Cross Ref]
374. Klammer M, Waterfall M, Samuel K, Turner ML, Roddie PH. Fusion hybrids of dendritic cells and autologous myeloid blasts as a potential cellular vaccine for acute myeloid leukaemia. Br J Haematol. 2005;129:340–9. doi: 10.1111/j.1365-2141.2005.05477.x. [PubMed] [Cross Ref]
375. Raje N, Hideshima T, Davies FE, Chauhan D, Treon SP, Young G, et al. Tumour cell/dendritic cell fusions as a vaccination strategy for multiple myeloma. Br J Haematol. 2004;125:343–52. doi: 10.1111/j.1365-2141.2004.04929.x. [PubMed] [Cross Ref]
376. Rosenblatt J, Vasir B, Uhl L, Blotta S, Macnamara C, Somaiya P, et al. Vaccination with dendritic cell/tumor fusion cells results in cellular and humoral antitumor immune responses in patients with multiple myeloma. Blood. 2011;117:393–402. doi: 10.1182/blood-2010-04-277137. [PMC free article] [PubMed] [Cross Ref]
377. Kikuchi T, Akasaki Y, Abe T, Fukuda T, Saotome H, Ryan JL, et al. Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12. J Immunother. 2004;27:452–9. doi: 10.1097/00002371-200411000-00005. [PubMed] [Cross Ref]
378. Avigan D. Fusions of breast cancer and dendritic cells as a novel cancer vaccine. Clin Breast Cancer. 2003;3(Suppl 4):S158–63. doi: 10.3816/CBC.2003.s.006. [PubMed] [Cross Ref]
379. Avigan D, Vasir B, Gong J, Borges V, Wu Z, Uhl L, et al. Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses. Clin Cancer Res. 2004;10:4699–708. doi: 10.1158/1078-0432.CCR-04-0347. [PubMed] [Cross Ref]
380. Barbuto JA, Ensina LF, Neves AR, Bergami-Santos P, Leite KR, Marques R, et al. Dendritic cell-tumor cell hybrid vaccination for metastatic cancer. Cancer Immunol Immunother. 2004;53:1111–8. doi: 10.1007/s00262-004-0551-7. [PubMed] [Cross Ref]
381. Haenssle HA, Krause SW, Emmert S, Zutt M, Kretschmer L, Schmidberger H, et al. Hybrid cell vaccination in metastatic melanoma: clinical and immunologic results of a phase I/II study. J Immunother. 2004;27:147–55. doi: 10.1097/00002371-200403000-00008. [PubMed] [Cross Ref]
382. Krause SW, Neumann C, Soruri A, Mayer S, Peters JH, Andreesen R. The treatment of patients with disseminated malignant melanoma by vaccination with autologous cell hybrids of tumor cells and dendritic cells. J Immunother. 2002;25:421–8. doi: 10.1097/00002371-200209000-00006. [PubMed] [Cross Ref]
383. Trefzer U, Herberth G, Wohlan K, Milling A, Thiemann M, Sharav T, et al. Tumour-dendritic hybrid cell vaccination for the treatment of patients with malignant melanoma: immunological effects and clinical results. Vaccine. 2005;23:2367–73. doi: 10.1016/j.vaccine.2005.01.081. [PubMed] [Cross Ref]
384. Trefzer U, Herberth G, Wohlan K, Milling A, Thiemann M, Sherev T, et al. Vaccination with hybrids of tumor and dendritic cells induces tumor-specific T-cell and clinical responses in melanoma stage III and IV patients. Int J Cancer. 2004;110:730–40. doi: 10.1002/ijc.20191. [PubMed] [Cross Ref]
385. Wei Y, Sticca RP, Holmes LM, Burgin KE, Li J, Williamson J, et al. Dendritoma vaccination combined with low dose interleukin-2 in metastatic melanoma patients induced immunological and clinical responses. Int J Oncol. 2006;28:585–93. [PubMed]
386. Papewalis C, Fassnacht M, Willenberg HS, Domberg J, Fenk R, Rohr UP, et al. Dendritic cells as potential adjuvant for immunotherapy in adrenocortical carcinoma. Clin Endocrinol (Oxf) 2006;65:215–22. doi: 10.1111/j.1365-2265.2006.02576.x. [PubMed] [Cross Ref]
387. Avigan D. Dendritic cell-tumor fusion vaccines for renal cell carcinoma. Clin Cancer Res. 2004;10:6347S–52S. doi: 10.1158/1078-0432.CCR-050005. [PubMed] [Cross Ref]
388. Dall’Oglio MF, Sousa-Canavez JM, Tanno FY, Tiseo BC, Crippa A, Dos Reis ST, et al. Early experience with targeted therapy and dendritic cell vaccine in metastatic renal cell carcinoma after nephrectomy. Int Braz J Urol. 2011;37:180–5, discussion 185-6. doi: 10.1590/S1677-55382011000200004. [PubMed] [Cross Ref]
389. Märten A, Renoth S, Heinicke T, Albers P, Pauli A, Mey U, et al. Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma. Hum Gene Ther. 2003;14:483–94. doi: 10.1089/104303403321467243. [PubMed] [Cross Ref]
390. Wei YC, Sticca RP, Li J, Holmes LM, Burgin KE, Jakubchak S, et al. Combined treatment of dendritoma vaccine and low-dose interleukin-2 in stage IV renal cell carcinoma patients induced clinical response: A pilot study. Oncol Rep. 2007;18:665–71. [PubMed]
391. Zhou J, Weng D, Zhou F, Pan K, Song H, Wang Q, et al. Patient-derived renal cell carcinoma cells fused with allogeneic dendritic cells elicit anti-tumor activity: in vitro results and clinical responses. Cancer Immunol Immunother. 2009;58:1587–97. doi: 10.1007/s00262-009-0668-9. [PubMed] [Cross Ref]
392. Homma S, Kikuchi T, Ishiji N, Ochiai K, Takeyama H, Saotome H, et al. Cancer immunotherapy by fusions of dendritic and tumour cells and rh-IL-12. Eur J Clin Invest. 2005;35:279–86. doi: 10.1111/j.1365-2362.2005.01494.x. [PubMed] [Cross Ref]
393. Homma S, Sagawa Y, Ito M, Ohno T, Toda G. Cancer immunotherapy using dendritic/tumour-fusion vaccine induces elevation of serum anti-nuclear antibody with better clinical responses. Clin Exp Immunol. 2006;144:41–7. doi: 10.1111/j.1365-2249.2006.03029.x. [PMC free article] [PubMed] [Cross Ref]
394. Apetoh L, Locher C, Ghiringhelli F, Kroemer G, Zitvogel L. Harnessing dendritic cells in cancer. Semin Immunol. 2011;23:42–9. doi: 10.1016/j.smim.2011.01.003. [PubMed] [Cross Ref]
395. Tsuji T, Matsuzaki J, Kelly MP, Ramakrishna V, Vitale L, He LZ, et al. Antibody-targeted NY-ESO-1 to mannose receptor or DEC-205 in vitro elicits dual human CD8+ and CD4+ T cell responses with broad antigen specificity. J Immunol. 2011;186:1218–27. doi: 10.4049/jimmunol.1000808. [PubMed] [Cross Ref]
396. Escudier B, Dorval T, Chaput N, André F, Caby MP, Novault S, et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med. 2005;3:10. doi: 10.1186/1479-5876-3-10. [PMC free article] [PubMed] [Cross Ref]
397. Sengar RS, Spokauskiene L, Steed DP, Griffin P, Arbujas N, Chambers WH, et al. Magnetic resonance imaging-guided adoptive cellular immunotherapy of central nervous system tumors with a T1 contrast agent. Magn Reson Med. 2009;62:599–606. doi: 10.1002/mrm.22030. [PMC free article] [PubMed] [Cross Ref]
398. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Xiangming C, Iwashige H, et al. Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer. Cancer Lett. 2000;159:103–8. doi: 10.1016/S0304-3835(00)00542-5. [PubMed] [Cross Ref]
399. Reichert TE, Scheuer C, Day R, Wagner W, Whiteside TL. The number of intratumoral dendritic cells and zeta-chain expression in T cells as prognostic and survival biomarkers in patients with oral carcinoma. Cancer. 2001;91:2136–47. doi: 10.1002/1097-0142(20010601)91:11<2136::AID-CNCR1242>3.0.CO;2-Q. [PubMed] [Cross Ref]
400. Ishigami S, Natsugoe S, Matsumoto M, Okumura H, Sakita H, Nakashima S, et al. Clinical implications of intratumoral dendritic cell infiltration in esophageal squamous cell carcinoma. Oncol Rep. 2003;10:1237–40. [PubMed]
401. Chang KC, Huang GC, Jones D, Lin YH. Distribution patterns of dendritic cells and T cells in diffuse large B-cell lymphomas correlate with prognoses. Clin Cancer Res. 2007;13:6666–72. doi: 10.1158/1078-0432.CCR-07-0504. [PubMed] [Cross Ref]
402. Jensen TO, Schmidt H, Møller HJ, Donskov F, Høyer M, Sjoegren P, et al. Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer. 2012;118:2476–85. doi: 10.1002/cncr.26511. [PubMed] [Cross Ref]
403. Iwamoto M, Shinohara H, Miyamoto A, Okuzawa M, Mabuchi H, Nohara T, et al. Prognostic value of tumor-infiltrating dendritic cells expressing CD83 in human breast carcinomas. Int J Cancer. 2003;104:92–7. doi: 10.1002/ijc.10915. [PubMed] [Cross Ref]
404. Ladányi A, Kiss J, Somlai B, Gilde K, Fejos Z, Mohos A, et al. Density of DC-LAMP(+) mature dendritic cells in combination with activated T lymphocytes infiltrating primary cutaneous melanoma is a strong independent prognostic factor. Cancer Immunol Immunother. 2007;56:1459–69. doi: 10.1007/s00262-007-0286-3. [PubMed] [Cross Ref]
405. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26:4410–7. doi: 10.1200/JCO.2007.15.0284. [PubMed] [Cross Ref]
406. Sautès-Fridman C, Cherfils-Vicini J, Damotte D, Fisson S, Fridman WH, Cremer I, et al. Tumor microenvironment is multifaceted. Cancer Metastasis Rev. 2011;30:13–25. doi: 10.1007/s10555-011-9279-y. [PubMed] [Cross Ref]
407. Sandel MH, Dadabayev AR, Menon AG, Morreau H, Melief CJ, Offringa R, et al. Prognostic value of tumor-infiltrating dendritic cells in colorectal cancer: role of maturation status and intratumoral localization. Clin Cancer Res. 2005;11:2576–82. doi: 10.1158/1078-0432.CCR-04-1448. [PubMed] [Cross Ref]
408. Correale P, Rotundo MS, Del Vecchio MT, Remondo C, Migali C, Ginanneschi C, et al. Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy. J Immunother. 2010;33:435–41. doi: 10.1097/CJI.0b013e3181d32f01. [PubMed] [Cross Ref]
409. Ladoire S, Martin F, Ghiringhelli F. Prognostic role of FOXP3+ regulatory T cells infiltrating human carcinomas: the paradox of colorectal cancer. Cancer Immunol Immunother. 2011;60:909–18. doi: 10.1007/s00262-011-1046-y. [PubMed] [Cross Ref]
410. Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer. 2000;89:2646–54. doi: 10.1002/1097-0142(20001215)89:12<2646::AID-CNCR18>3.0.CO;2-A. [PubMed] [Cross Ref]
411. Guo J, Zhu J, Sheng X, Wang X, Qu L, Han Y, et al. Intratumoral injection of dendritic cells in combination with local hyperthermia induces systemic antitumor effect in patients with advanced melanoma. Int J Cancer. 2007;120:2418–25. doi: 10.1002/ijc.22551. [PubMed] [Cross Ref]
412. Chi KH, Liu SJ, Li CP, Kuo HP, Wang YS, Chao Y, et al. Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. J Immunother. 2005;28:129–35. doi: 10.1097/01.cji.0000154248.74383.5e. [PubMed] [Cross Ref]
413. Finkelstein SE, Iclozan C, Bui MM, Cotter MJ, Ramakrishnan R, Ahmed J, et al. Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Int J Radiat Oncol Biol Phys. 2012;82:924–32. doi: 10.1016/j.ijrobp.2010.12.068. [PMC free article] [PubMed] [Cross Ref]
414. Mann DL, Celluzzi CM, Hankey KG, Harris KM, Watanabe R, Hasumi K. Combining conventional therapies with intratumoral injection of autologous dendritic cells and activated T cells to treat patients with advanced cancers. Ann N Y Acad Sci. 2009;1174:41–50. doi: 10.1111/j.1749-6632.2009.04934.x. [PubMed] [Cross Ref]
415. de Vries IJ, Tel J, Benitez-Ribas D, Torensma R, Figdor CG. Prophylactic vaccines mimic synthetic CpG oligonucleotides in their ability to modulate immune responses. Mol Immunol. 2011;48:810–7. doi: 10.1016/j.molimm.2010.12.022. [PubMed] [Cross Ref]
416. Schreibelt G, Benitez-Ribas D, Schuurhuis D, Lambeck AJ, van Hout-Kuijer M, Schaft N, et al. Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells. Blood. 2010;116:564–74. doi: 10.1182/blood-2009-11-251884. [PubMed] [Cross Ref]
417. Kroemer G, Zitvogel L. Can the exome and the immunome converge on the design of efficient cancer vaccines? OncoImmunology. 2012;1 In press. [PMC free article] [PubMed]
418. Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell. 2012;148:886–95. doi: 10.1016/j.cell.2012.02.025. [PubMed] [Cross Ref]
419. Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, et al. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat Biotechnol. 2012;30:337–43. doi: 10.1038/nbt.2157. [PMC free article] [PubMed] [Cross Ref]
420. Castle JC, Kreiter S, Diekmann J, Löwer M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72:1081–91. doi: 10.1158/0008-5472.CAN-11-3722. [PubMed] [Cross Ref]
421. de Vries IJ, Lesterhuis WJ, Barentsz JO, Verdijk P, van Krieken JH, Boerman OC, et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat Biotechnol. 2005;23:1407–13. doi: 10.1038/nbt1154. [PubMed] [Cross Ref]
422. Tel J, van der Leun AM, Figdor CG, Torensma R, de Vries IJ. Harnessing human plasmacytoid dendritic cells as professional APCs. Cancer Immunol Immunother. 2012 doi: 10.1007/s00262-012-1210-z. [PMC free article] [PubMed] [Cross Ref]
423. Michaelis LC, Ratain MJ. Measuring response in a post-RECIST world: from black and white to shades of grey. Nat Rev Cancer. 2006;6:409–14. doi: 10.1038/nrc1883. [PubMed] [Cross Ref]
424. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. doi: 10.1056/NEJMoa1003466. [PMC free article] [PubMed] [Cross Ref]
425. de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ, et al. Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res. 2003;9:5091–100. [PubMed]
426. Paczesny S, Banchereau J, Wittkowski KM, Saracino G, Fay J, Palucka AK. Expansion of melanoma-specific cytolytic CD8+ T cell precursors in patients with metastatic melanoma vaccinated with CD34+ progenitor-derived dendritic cells. J Exp Med. 2004;199:1503–11. doi: 10.1084/jem.20032118. [PMC free article] [PubMed] [Cross Ref]
427. Welters MJ, Kenter GG, de Vos van Steenwijk PJ, Löwik MJ, Berends-van der Meer DM, Essahsah F, et al. Success or failure of vaccination for HPV16-positive vulvar lesions correlates with kinetics and phenotype of induced T-cell responses. Proc Natl Acad Sci U S A. 2010;107:11895–9. doi: 10.1073/pnas.1006500107. [PMC free article] [PubMed] [Cross Ref]

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