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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Immunol Res. Author manuscript; available in PMC Jun 28, 2013.
Published in final edited form as:
PMCID: PMC3695396
NIHMSID: NIHMS419264

Dendritic cells in cancer immunotherapy: vaccines or autologous transplants?

Abstract

Dendritic cells (DCs) are the most powerful immunostimulatory cells specialized in the induction and regulation of immune responses. Their properties and the feasibility of their large-scale ex vivo generation led to the application of ex vivo-educated DCs to bypass the dysfunction of endogenous DCs in cancer patients and to induce therapeutic anti-cancer immunity. While multiple paradigms of therapeutic application of DCs reflect their consideration as cancer “vaccines”, numerous features of DC-based vaccination resemble those of autologous transplants, resulting in challenges and opportunities that distinguish them from classical vaccines. In addition to the functional heterogeneity of DC subsets and plasticity of the individual DC types, the unique features of DCs are the kinetic character of their function, limited functional stability, and the possibilitytoimprint in maturing DCs distinct functions relevant for the induction of effective cancer immunity, such as the induction of different effector functions or different homing properties of tumor-specific T cells (delivery of “signal 3” and “signal 4”). These considerations highlight the importance of the application of optimized, potentially patient-specific conditions of ex vivo culture of DCs and their delivery, with the logistic and regulatory implications shared with transplantation and other surgical procedures.

Keywords: Dendritic cells, IL-12, Immunotherapy, Cancer, Vaccines, Cytokines, Chemokines, Chemokine receptors, Th1, CTL, NK, Treg

DCs and cancer immunotherapy

Despite advances in cancer prevention and therapy, resulting in the recent decrease in cancer-related death rates, cancer remains a leading cause of mortality in the developed world [1]. Many groups of cancer patients and especially patients with advanced disease lack not only curative therapies, but also treatment options that offer significant impact upon cancer progression and symptom palliation. Standard therapies are effective in eliminating tumor bulk, but often lack the capacity to eliminate residual cancer cells and to prevent cancer recurrence. This particular deficit provides the rationale to include the means to mobilize the antitumor functions of immune system that specializes in eliminating rare “non-self” cells, in comprehensive cancer care. Following the original demonstration by William B. Coley that the immune system can be mobilized to fight established cancer [2, 3], massive research efforts of the past century helped to develop an understanding of the basic paradigms of immune recognition and elimination of tumor cells, facilitating the clinical introduction of multiple forms of cancer immunotherapy. Within the last 12 months alone, three novel therapies, Sipuleucel-T (Provenge; Dendreon), a cellular product involving antigen-loaded DCs and T cells [410], and Ipilimumab (Bristol-Myers Squibb), an antibody blocking the CTLA-4-mediated suppressive events [11], as well as pegylated IFNα (peginterferon alfa-2b, Sylatron; Schering) have been approved by the FDA for the treatment of advanced prostate cancer and melanoma, reflecting the increasing contribution of immunotherapy to cancer management [11, 12].

In contrast to non-specific immunotherapies (adjuvants, cytokines, and checkpoint blockade) that activate multiple cell types (tumor, stroma, and different subsets of immune cells), therapeutic cancer vaccines attempt to instruct selected tumor-specific immune system to kill cancer cells. This narrow focus offers unique advantages of low toxicity and prolonged effects (immunosurveillance), due to the selective activation of relatively few, but long-lived tumor-specific memory cells. While most types of vaccines, involving antigenic peptides, proteins or genetically modified tumor cells or viruses, all depend on antigen cross-presentation by patients’ endogenous DCs, the dysfunction of DCs in cancer patients [1318] suggested the use of ex vivo-generated DCs as superior inducers of immune response [19]. DCs, discovered by Ralph M. Steinman in 1970s [2023], are antigen-presenting cells uniquely specialized in inducing primary immune responses, supporting survival and effector functions of previously primed T cells, as well as mediating effective communication between other components of the immune system [24, 25]. Importantly for their clinical application, human DCs can be generated in large numbers from blood [26, 27] or bone marrow [28] progenitors. Since, in contrast to endogenous DCs in cancer patients that develop in the presence of tumor-associated suppressive factors [1318], mature DCs acquire significant resistance to suppression [2931], ex vivo-generated functional DCs have been introduced as immunization tools.

Despite the early promise of DCs in inducing antitumor responses and delaying cancer progression [3235], the overall effectiveness of the currently available DC vaccines (and other therapeutic vaccines against cancer) remains dramatically lower than the effectiveness of protective vaccines against infectious agents and tumors caused by such agents [12, 3643]. In particular, despite the ability of therapeutic vaccines to stabilize cancer progression and/or prolong patients’ survival [5, 41, 4446], their effectiveness in inducing regression of bulky tumors, as measured by RECIST or WHO criteria, remains low [5, 33, 40, 44, 45, 47].

Limits of the vaccine paradigm

Protection versus therapy

Comparison of the goals and challenges facing the therapeutic use of DCs and the traditional use of protective vaccines reveals significant differences. While some goals of “therapeutic vaccines” are shared with protective vaccines (for example the need to induce high numbers of T cells specific against unique antigens: delivery of “signal 1” and “signal 2” [12, 36, 4749]), several aspects of vaccination in therapeutic settings pose additional challenges in patients with advanced cancer (Figs. 1, ,2):2): In contrast to recall responses to tissue-invading microorganisms, the vaccination-induced T cells of cancer patients are not exposed to pro-inflammatory alarm signals from infected tissues and innate immune cells, known to facilitate the development of effector functions and attracting effector cells to the sites of pathogen entry. This introduces more stringent requirements for therapeutic vaccines, which in addition to driving the expansion of cancer-specific T cells, also need to substitute for the missing pathogenic challenge and acute inflammatory response which are critical to promote T-cell cytolytic effector functions and their acquisition of peripheral homing function [5056]. In addition, in contrast to viral and bacterial infections that act as sources of the effector cell-attracting chemokines at the sites of pathogen entry [48, 54, 57], therapeutic vaccines either need to induce T cells that respond to the chemokines spontaneously expressed by tumors (that themselves use chemokines for growth, metastatic spread, and survival [5863]), or be combined with additional factors able of modulating tumor-associated chemokine environments.

Fig. 1
Ability of DCs to regulate different aspects of T cell activity. DCs provide T cells with antigenic “signal 1” and costimulatory “signal 2” needed for the activation and expansion of tumor-specific CD4+ and CD8+ T cells. ...
Fig. 2
Unique goals and challenges of DC therapies. In contrast to preventive vaccines, therapeutic application of antigen-loaded DCs needs to overcome tumor-induced dysfunction of endogenous DCs and the presence of tumor-induced suppressive immune cells, such ...

Furthermore, therapeutic cancer vaccines need to function in the presence of an established tumor mass and tumor-induced immune dysfunction, associated with the expansion and hyperactivation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) [6467]. Patients with melanoma, ovarian-, breast-, renal, prostate-, lung- and head-and-neck-cancer also show profound dysfunction of endogenous DCs and other antigen-presenting cells (APCs), and overproduction of the factors that suppress the functions of endogenous or adoptively transferred DCs: IL-10, TGF-β, VEGF, IL-6, and COX2 products (such as PGE2) [1318, 49, 6877]. In contrast to the developing DCs, fully mature DCs acquire significant resistance to such inhibitory factors [2931], providing the rationale for the ex vivo generation of DCs for the therapy of cancer patients. Unfortunately, while pre-existing Tregs are known to limit the effectiveness of cancer vaccines [66, 78], Treg numbers can be even further expanded by the some of the previously tested DC vaccines [67, 79].

The above data raise concerns whether the traditional paradigms developed based on experience with protective vaccines are indeed relevant or sufficient to the development of therapeutic vaccines against cancer.

DCs versus other immunogens

In addition to the above challenges related to their application in therapeutic settings, dendritic cells also differ from traditional vaccines with regard to their physical character. The use of autologous live cells as a source of immunogenic signals offers several distinct advantages compared with such stabilized forms of antigens as proteins, peptides or even genetically modified viruses or tumor cells. The main advantage of DC therapy is that while all the latter immunogens rely on their cross-presentation by endogenous APCs, ex vivo generation of the DCs allows avoiding endogenous DC dysfunction. Direct presentation of antigen by the ex vivo-generated DCs also facilitates the delivery to T cells of the most desirable signals that can be imprinted in DCs by the conditions of their development and maturation (see below). In addition, the ex vivo loading of tumor-associated antigens facilitates their selective delivery to DCs and limits their presentation by non-professional APCs or tumor-affected endogenous DCs, both of which can be tolerogenic.

At the same time, immunization with live cells needs to take into account the limited stability of their functions over time [29, 8082], their limited life span in vivo and the possibility of their elimination by pr-existing effector T cells (induced by the growing tumors or active immunization) [8388]. Since DC immunization aims to deliver not only antigen, but also additional information required by T cells (see below), this form of therapy makes sense mostly if the original DCs (rather than antigens released from DCs) are able to contact the lymph node-based T cells.

Effectiveness of delivery to the lymph nodes and DC dosage

The limited functional life span of migrating DCs and the eventual “exhaustion” of their cytokine-producing function [29, 8082] suggest the importance of the route of DC delivery, which should allow their entry into lymph nodes within short period of time after injection. Unfortunately, the efficacy of the most frequently used routes of DC delivery (i.d. or s.c) allows only 0.1–2% of injected DCs to ever reach the vaccine-draining LNs, with the majority of the DCs reaching the lymph nodes only after the 24–48 h [8992]. While the traditional solution to this problem has been the administration of high numbers of DCs (3× [106] to 30× [106], and sometimes exceeding 100× [106] cells per injection), such an approach cannot compensate for the delayed arrival of DCs to the nodes, at time points known to be associated with significant reduction of DCs ability to produce Th1 cell- and CTL-activating cytokines (DC “exhaustion”) [29, 8082]. Moreover, administration of large numbers of DCs increases the chances of the uptake of cancer-associated antigen released from DCs by endogenous, cancer-suppressed DCs and other non-professional APCs.

Another consideration is an identification of an optimal dose of DCs for effective immunization. The method of long-term cannulation of human afferent lymphatic vessels [9395] allowed demonstrating that the development of even such powerful responses as contact allergy [9698] involves no more than several hundred thousand DCs per day [97]. While for most of cancer therapeutic agents, the higher dose (close to the maximal tolerated dose; MTD) is presumed to be better, resulting in the typical pattern of phase 1 studies that aim to identify the MTD, the same assumption may not be valid for DCs, due to potential phenomena of high-dose tolerance [99, 100] and undesirable cross-presentation of DC-carried antigens by endogenous cells.

Duration of DC delivery and their persistence in lymph nodes

The induction of allergic reaction to DNCB is associated with the continued lymph flow of antigen-containing endogenous DCs for at least 22 h after antigen application (although no longer at 51 h) [97]. Since activated T cells require prolonged TCR occupancy to assure effective T-cell activation and development of memory and effector functions [101106], and effective preventive vaccines are known to require prolonged antigen release (depot effect) [107, 108], the effectiveness of DC vaccines is also likely to depend on the prolonged presence of DCs in the lymph nodes. In contrast to classical vaccines (peptides, proteins), which release the antigens in a prolonged fashion, the stability of DC-expressed peptide/MHC complexes, as well as the functional stability of DCs and their overall survival, are limited. These considerations suggest that in contrast to typical vaccines, the immunogenic activity of antigen-loaded DC may benefit from their repetitive administration over each course of immunization and from their protection from exhaustion and apoptosis. In line with this possibility, mouse studies have documented that transfection with antiapoptotic genes [109], inhibitors of pro-apoptotic genes [110, 111], or survival factors such as GM-CSF, all increase the ability of adoptively transferred DCs to induce therapeutic anti-tumor immunity [112], while additional advantage can be offered by extending the duration of antigen persistence within DCs [113].

Autologous cells versus off-the-shelf vaccines: Logistic and regulatory issues

Typical vaccines, even vaccines containing live organisms (modified viruses or bacteria) can be mass-produced and effectively preserved, allowing their prolonged shelf life and widespread distribution. The use of standardized resources and uniform operating procedures (SOPs) allow high batch-to-batch uniformity.

In contrast, several aspects of production and administration of DCs resemble the steps involved in bone marrow- or pancreatic islets transplantation, or blood transfusion. Since the process starts with a patient-specific population of precursor cells, even strict adherence to SOPs during DC generation cannot guarantee the uniform quality of different batches of DCs, nor their uniform numbers, which may be intrinsically different between patients.

These considerations raise the possibility that the optimal quality of the cellular product for each individual patient may benefit from the use of flexible or alternative SOPs, which would allow adjustment of the process of DC generation (for example the duration of DC maturation or its specific conditions), based on the quality of the precursor cells, interim analysis of the product, or a small-scale test run to identify the most-effective option. Furthermore, the resulting cellular product shows relatively limited stability, and while it can be cryopreserved, its final processing and administration needs to take into account the changing functions of DCs prior to and after administration to patients, and the need to achieve the DC-T-cell contact within short period of time following injection, resulting in the importance of the mode of DC application. Therefore, taking autologous DC therapies to the level of “personalized” medicine, based on patient-specific cellular makers, may allow them to fully realize their potential.

From the regulatory standpoint, these considerations raise the question whether DC therapies are a vaccine product or a medical procedure. While the complexity of cellular manipulation of DCs is higher compared with bone marrow transplant, cellular therapies with DCs do not involve the risks associated with myeloablative conditioning regimens, and as autologous cells, have significantly lower risks and minimal or absent toxicity.

Making the most of DCs: exploiting signal 1, signal 2, signal 3, and signal 4

Generation of DCs ex vivo allows their loading with the desirable antigens, in order to assure effective delivery of “signal one” and “signal two” (antigen and costimulation) [114116] to tumor-specific T cells (Fig. 2). It also allows imprinting additional DC features important for effective cancer immunity, such as their ability to preferentially interact with selected subsets of immune cells (effector rather than regulatory), induce desirable effector mechanisms (delivery of “signal three”) [25] to selectively enhance the Th1-, CTL- and NK cell-mediated type-1 immunity [25, 114123], desirable in cancer [124], and to enhance the tumor-relevant homing properties of activated T cells (delivery of “signal four”) [125].

Delivery of antigen (signal 1)

DCs are specialized in cross-presentation of different forms of antigen, including whole tumor cells [49, 126128]. These properties allow the use of not only peptides or recombinant proteins, but also allogeneic or autologous tumor material as the source of DC-cross-presented antigen [129], allowing for application of DCs against tumors with undefined tumor-rejection antigens and to immunize against unique patient-specific antigens. However, the ability to cross-present antigens differs between different DC subsets, stages of DC development and maturation, and is affected by the conditions of DC activation/maturation [130133]. While the early stages of DC maturation are in general believed to be optimal for antigen uptake and its cross-presentation [27, 134136], the effectiveness of tumor cell cross-presentation can be significantly affected by the selection of factors that are used in the maturation of DCs [137].

Costimulatory molecules (signal 2) and lymph node-homing: Role of DC maturation

Effective induction of anti-tumor CTL responses requires mature DCs that express high levels of costimulatory molecules and which can migrate in response to CCL19 or CCL21, the lymph node-produced CCR7 ligands [89, 90, 138, 139]. In order to overcome the limitations of immature or partially mature DCs (constituting the “first generation” of DC vaccines), numerous protocols were developed to induce fully mature DCs for clinical use. Initially, two modalities involving PGE2: monocyte-conditioned medium [140, 141] and a cytokine cocktail involving IL-1β, TNFα, IL-6, and PGE2[142] were used to induce mature DCs with high expression of co-stimulatory molecules and CCR7 (and the high migratory responsiveness to lymph-node-produced chemokines CCL19 and CCL21) [143, 144]. The IL-1β/TNFα/IL-6/PGE2-matured DCs [142] showed enhanced immunogenicity in vitro and in vivo in healthy volunteers, [90, 138] as well as improved migratory responses to LN-associated chemokines, when compared with immature DCs [89, 143, 144], and have been tested in numerous clinical trials. Unexpectedly, their randomized comparison with dacarbazine in a III trial in advanced melanoma showed very limited ability to induce clinical responses (less than 5%) and the lack of detectable impact on patients’ survival [145]. While additional factors, such as the preparation of DC in different laboratories, might have negatively affected the results of this multi-center trial, the negative impact of PGE2 on the production of IL-12p70 [30, 31, 146, 147] (central to the induction and survival of type-1 immune cells) [120] is a possible culprit. These clinical data highlight the functional importance of the ability of DCs to produce IL-12p770, which has been demonstrated to be the best indicator of anti-tumor potency of DCs in vitro [148, 149] and in vivo [46] identified to date.

Induction of anti-tumor effector functions (signal 3)

The character of immune response (its Th1 dominance and avoidance of Treg activation), rather than its magnitude, has been shown to predict therapeutic activity of vaccination in mouse [124]. In accordance with these data, high secretion of IL-12p70 has been shown to strongly enhance DCs ability to induce tumor-specific Th1 cells and CTLs, and to promote tumor rejection in therapeutic models [150160]. These murine model data have been more recently supported by human preclinical and clinical studies, demonstrating that the ability of antigen-loaded DCs to produce IL-12p70 is the predictive indicator of their ability to induce tumor-specific CTLs in vitro [148, 149] and clinical benefits in vivo [46].

Unfortunately, the “second-generation” DCs, matured in the presence of an IL-1β/TNFα/IL-6/PGE2-containing cytokine cocktail [142], showed a reduced ability to produce bioactive IL-12p70, and the phenomenon is referred to as DC “exhaustion” [29, 80, 161]. In an attempt to boost the clinical efficacy of cancer vaccines, we and other groups have demonstrated the feasibility of inducing “non-exhausted” mature DCs, by exposing immature DCs to type-1 and type 2 interferons and TLR ligands, or alternatively, to IL-18-activated NK cells or memory-type CD8+ T cells [30, 161168]. The resulting “type-1 polarized” DCs (DC1) show a strongly enhanced capacity to induce long-lived tumor-specific T cells with pronounced anti-tumor effector functions in human in vitro and mouse in vivo models, as well as enhancement of tumoricidal functions in resting NK cells. Our initial studies [30, 161] and the data from other laboratories [166, 169] showed that the combination of IFN-γ with LPS (or its clinically compatible form, MPLA), or with TNFα and IL-1β can overcome the maturation-associated DC “exhaustion”, resulting in polarized DC1s that produce elevated levels of IL-12p70 upon interaction with CD40L-expressing CD4+ Th cells and induce stronger Th1 and CTL responses [30, 166]. The additional presence of IFNα and polyinosinic:polycytidylic acid (poly-I:C; TLR3 ligand) in the maturation-inducing cocktail, further enhances the ability of maturing DC1s to express CCR7 [161], and instructs them to preferentially interact with naïve, memory, and effector T cells, rather than with the undesirable Tregs[147] (see below). In accordance with the ability of polarized DCs to induce qualitatively improved immune responses, “alpha-type-1-polarized DCs” (αDC1s) induce on average 20-fold higher numbers of long-lived functional melanoma-specific CTLs in a single round of in vitro sensitization [161] when compared with the DCs matured by IL-1β/TNFα/IL-6/PGE2[142]. So far, our data from melanoma [161], CLL [170], prostate [171], glioblastoma [46] and several other cancers uniformly demonstrate the feasibility of generating type-1-polarized DCs from patients with advanced cancer, their loading with peptide antigens [46, 161] or apoptotic tumor cells [137, 170, 171] and their effectiveness in inducing tumor-specific CTLs. In addition, it was recently demonstrated that αDC1s also show superior activity in activating NK cells [172]. While our own work focused on IFNα-supported DC1s (αDC1s) [161, 167] and DC1s induced by autologous NK cells or memory CD8+ T cells [164, 165, 168], several other groups [166, 167, 169] showed the feasibility of generating clinical-grade DC1s using the combination of IFN-γ with MPLA, a “detoxified” form of LPS [30, 166, 167, 169] and on alternative ways of enhancing the desirable properties of DCs (that could be combined with DC1 polarization), such as the use of IL-15 (instead of IL-4) to promote early DC development [173], B7-DC-cross-linking [174], inhibition of p38MAPK [175, 176] or genetic manipulation of DCs to over-express t-bet.

While polarized and non-polarized DCs both effectively induce the expansion of naïve CD8+ T cells and their CD45RA to CD45RO conversion, polarized DC1s show advantage in inducing T-cell expression of granzyme B and perforin, and their cytolytic activity against tumor targets. The advantage of DC1s in inducing qualitatively superior CTLs was observed both in the case of polyclonally activated naïve cells, and recall responses to tumor-specific antigens (such as MART-1), but DC1 involvement was particularly important for naïve cells, suggesting their key role in the de novo CTL induction, rather than selection of the previously induced CTLs.

Cumulatively, these data suggest that the effectiveness of DCs as inducers of antitumor responses can be modulated by the factors regulating their ability to produce IL-12p70 (and possibly other Th1-, CTL- and NK cell-activating cytokines). We are currently evaluating this hypothesis in phase I/II trials in patients with cutaneous T-cell lymphoma, glioma, colon and prostate cancers, as well as melanoma (respectively, NCT00099593, NCT00766753, NCT0055 8051, NCT00970203, and NCT00390338). The recently completed phase I/II trial in patients with the recurrent high-grade malignant glioma demonstrated the ability to prolong the progression free survival (PFS) to at least 12 months (compared with the expected PFS of 3–4 months for this patient group) in 9 of 22 patients [46, 82, 177]. Radiological tumor shrinkage was observed in two of these patients. Importantly, the ability of the individual αDC1 vaccines to produce IL-12p70 was the best predictive marker of the prolonged PSF in the individual patients [46].

Induction of tumor-homing properties in tumor-specific T cells (signal 4)

While the activation of naïve T cells is generally considered to be associated with the acquisition of their ability to home peripheral tissues, T-cell activation by different types of DCs has been shown to be associated with the induction of their different homing patterns in mouse models [178184]. Importantly for the application of human differentially matured DCs in cancer immunotherapy, the MART-127–35-specific CD8+ T cells from HLA-A2+ melanoma patients sensitized by polarized DC1 showed elevated levels of CCR5 (receptors for CCR1, CCR2, and CCR5) and CXCR3 (receptor for CXCL9, CXCL10 and CXCL11), the peripheral tissue-type chemokine receptors involved in the T-cell entry into melanomas and other tumors [59, 82, 185188], compared with the cells sensitized by and nonpolarized DCs.

Programming the DCs to interact with desirable types of immune cells

Several recent trials demonstrated that standard DC vaccines may promote the undesirable expansion of Treg cells in cancer patients [67, 79, 82, 189191], raising the question whether the pattern of interaction of DCs with Tregs (and resulting Treg activation) can be modulated independently from the DC interaction with naïve, central memory, and effector cells.

Consistent with such possibility, the elimination of PGE2 and inclusion of IFNα in the DC-maturation cocktails is the enhanced production of CXCL9, CXCL10, CXCL11, and CCL5 by resulting mature DCs and their decreased production of CCL22, promoting their interaction with the desirable, CXCR3- and CCR5-expressing CTLs, Th1, and NK cells, and to avoid the attraction of Tregs and other suppressor cells known to express CCR4 (receptor for CCL22) [92, 147, 172]. The observed stability of such maturation-induced differences in chemokine profiles of DCs [92, 147] suggests that the differentially matured DCs can be used to selectively expand these subsets and/or support their functions.

Promoting rapid delivery of DCs to the lymph nodes: Immunotherapy in surgical context

Accelerated delivery of DCs to T-cell-containing lymph nodes may enhance their immunologic and clinical activity, by limiting the time-associated exhaustion of their IL-12p70-producing function. Ultrasound-guided intranodal injection of DCs represents the most direct way of promoting rapid contact of DCs with the lymph node–based T cells and has been used in multiple clinical trials. Unfortunately, as showed by Jolanda de Vries and colleagues, even highly trained radiologists can miss the lymph node or deliver the DCs superficially, resulting in their expulsion from the lymph node and peri-nodal localization in up to 40% of injections, limiting the effectiveness of this procedure [192]. The direct intranodal route also makes it difficult to (re)administer multiple doses of DCs, due to the logistical limitations (need r for a trained radiologist for each injection) and progressive structural damage to the targeted lymph nodes.

Driven by past utilization of intralymphatic injections as a way to deliver DCs [166, 193197] and other immunomodulators [198200], and the feasibility of long-term lymphatic annulations to harvest lymph-born DCs [9398], we tested the feasibility of prolonged semi-continuous intralymphatic delivery of antigen-loaded DCs in two clinical trials in colorectal cancer and melanoma. This method has been successfully applied in over 20 cancer patients, allowing reliable delivery of multiple doses of low numbers of antigen-loaded DCs (12 injections per course; 25,000 or 250,000 DCs per injection) over a 4-day-long course of vaccination. The possibility of repetitively administering DCs directly into the lymphatics over prolonged periods of time obviates many of the logistic and biologic problems associated with the direct intranodal injections. It also allows for the delivery of DCs in combination with factors that regulate their in vivo production of different classes of T-cell-activating, T-cell-attracting and T-cell-regulating factors.

Vaccination or autologous transplantation?

The biology of DCs, their adaptability to environmental conditions, and the “kinetic” character of their functions create unique opportunities as well as logistic and regulatory challenges, differentiating DC therapies from other forms of immunization. In contrast to standardized off-the-shelf vaccines, the therapeutic application of DCs needs to accommodate the intrinsic differences of the cells generated from different patients, the changing functions of DCs prior to and after their administration, and the need to assure the ability of DCs to interact with T cells within a short period of time following injection. On the other hand, the use of ex vivo-matured DCs uniquely allows to bypass the dysfunction of the endogenous APCs in cancer-bearing patients and deliver to the lymph nodes additional pro-inflammatory signals, (“signal 3” and “signal 4”) typically provided by infectious agents themselves but missing in the settings of cancer. These considerations highlight the analogy to several aspects of transplantation, similarly aiming to restore lost functionality of an organ or system, and implicate that a personalized approach to DC therapies may help to fully realize their therapeutic potential.

Acknowledgments

Support by the NIH grants CA095128, CA114931, CA121973, CA137214 and CA138639, is acknowledged.

Contributor Information

Pawel Kalinski, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

Howard Edington, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

Herbert J. Zeh, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

Hideho Okada, Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

Lisa H. Butterfield, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

John M. Kirkwood, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

David L. Bartlett, Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. University of Pittsburgh Cancer Institute, Hillman Cancer Center, University of Pittsburgh, UPCI Research Pavilion, Suite 1.46, 5117 Center Ave, Pittsburgh, PA 15213-1863, USA.

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