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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 63Cytokines: Biology and Applications in Cancer Medicine

, PhD.

Cytokines are a large family of soluble proteins, which include the clinically relevant immune system regulators, the interleukins (ILs). The interleukins are regulators of the immune system, which with some success have been used in cancer therapy during attempts to elicit immune activation. From an immunologic perspective, the very fact that metastatic human cancers exist indicates that they have evaded an effective immune response. Presuming that antigens exist on tumor cells, various cytokines, and particularly interleukins, are now administered to patients in an attempt to initiate, augment, or otherwise stimulate an antitumor immune response. In addition to immune response stimulation, some interleukins have been used to stimulate the growth and differentiation of various subpopulations of blood cells after chemotherapy, or bone marrow transplantation. In a large series of recently reported findings, it is now appreciated that both lymphoid as well as solid tumors can express and secrete interleukins, the extent of which is yet to be realized; the study of anomalous expression of immune regulators is becoming a most active area in tumor immunology research. In spite of our minimal knowledge of cytokine biology, observations of regression of metastatic cancer in humans as a result of interleukin administration provides a compelling impetus for their continued study. The biologic characterization of the known clinically relevant interleukins and selected cytokines, the rationales for their use in therapy of patients with cancer, and the accumulated clinical experience represent the subjects of this chapter. The presentation of each cytokine proceeds in an approximately chronological order of the initial clinical trial consideration. Therefore, IL-2 which is the only interleukin officially approved for clinical use is described first, followed by IL-12, TNF-α, IL-1, IL-6, IL-4, colony-stimulating factors (CSFs), IL-10, IL-13, and IL-15.

The term interleukin is used to designate any soluble protein or glycoprotein product of leukocytes that regulates the responses of other leukocytes. As hormones of the immune response, interleukins produce their effects primarily through paracrine interactions. The cascades of interleukins that are generated by both pathogen exposure and antigen-specific interactions are primarily local, with the functions of individual interleukins mediated by paracrine interaction with specific receptors expressed differentially on different cell types, including hematopoietic and immunologic cells but also including endothelial and other cells. The paracrine immune effects of these interleukins include the initiation, amplification, maintenance, and termination of various phases of the immune response. Potent systemic effects are also observed with the interleukins through their interactions with cells of the vascular endothelium, fibroblasts, keratinocytes, adipocytes, and the central nervous system. Interleukins are designated by the “IL” followed by their designated number in order of discovery, which as of 1999, are numbered officially from 1 to 18, with IL-19 and IL-20 mentioned but not officially sanctioned. Clinical trials have been initiated with those up to IL-15; and IL-18, the interferon (IFN)-α–inducing factor, being used in preclinical testing at this time.


Biology and Preclinical Rationale

Interleukin-2 (IL-2) was originally described in 1976 as the T-cell growth factor, as it was recognized for its ability to support the growth of T lymphocytes.1 IL-2, together with IFN-α represent the major cytokine products of the Th1 helper cells induced by antigen and IL-12 and counter-regulated by the Th2 cytokines IL-4 and IL-10.2,3 IL-2 is a 133 amino acid glycoprotein of 15-kd molecular weight and contains an intrachain disulfide bond. Through interaction with a specific receptor located on T cells, B cells, macrophages, and natural killer (NK) cells, IL-2 plays a central role in the maturation and development of lymphocytes and monocytes.

The IL-2 receptor complex is composed of at least three subunits, an α chain (p55, Tac), a β chain (p75), and the more recently described γ chain (p64), this last being a common component of receptors for numerous other cytokines.4,5 The different subunits have different functions, with the α chain being responsible for the rapid association with IL-2 and the β–γ complex responsible for the long dissociation time; the net result is a highly specific, trimeric receptor of high affinity (kd, 10-11) for IL-2 expressed on a narrow range of cell types.6 Following binding of IL-2 with the trimeric receptor complex, internalization occurs and cell cycle progression is induced, in association with the expression of a defined series of genes.7 A second functional response occurs through the IL-2 receptor ß-γ dimeric receptor, also known as the intermediate affinity dimeric complex (kd, 10-9) and involves the differentiation of several subclasses of lymphocytes into lymphokine-activated killers (LAKs). This response occurs in patients with cancer who receive IL-28,9 and was originally considered to be a critical part of the anticancer effect of IL-2. LAKs recognize and kill tumor cells irrespective of the histocompatibility expression status on fresh human tumor cells tested.10 The multiple biologic effects of IL-2 on immune cells include the induced proliferation of antigen-stimulated T cells and induction of cytotoxicity in major histocompatibility complex (MHC)-restricted, antigen-specific T lymphocytes, NK cells leading to non–MHC-restricted LAK activity, and activation of tumoricidal monocytes; it is not clear what role any of these effector systems have in vivo.11,12 The reproducible observations that virtually all malignant cells can be lysed by IL-2 stimulated lymphocytes in a manner directly related to the intensity of IL-2 administration encouraged the pursuit of aggressive, intensive clinical trials involving IL-2 in patients with cancer.

Clinical Applications Renal Cell Carcinoma

IL-2 (Aldesleukin, Proleukin) is now approved by the U.S. Food and Drug Administration (FDA) and by regulatory authorities in Canada and the European Community for the treatment of patients with metastatic renal cell carcinoma and melanoma. The database for approval in the United States included 255 patients treated in seven separate clinical studies that used a treatment regimen developed in the Surgery Branch of the National Cancer Institute (NCI); recombinant IL-2 administered at a dose of 600,000 or 720,000 IU/kg by 15-minute bolus infusion every 8 hours to tolerance from days 1 to 5 and repeated on days 15 to 19.13-20 The overall response rate among patients with renal cell carcinoma was 14%, with 4% of patients achieving complete regression.21 Although these response rates are modest, the prolonged median duration of all responses (approximately 20 months) and the apparent permanence of most complete responses in a population of patients with advanced progressive renal cell carcinoma were felt to represent evidence for significant benefit to patients. As of 1999, 15 to 20% response rates continue to be observed in the various trials, suggesting that additional approaches are warranted.22 Responses occurred at all treated sites, including the liver, adrenal glands, and the renal primary and renal bed recurrences, although most responses were found in patients with lung or lymph node metastatic disease.

High-dose bolus IL-2 regimen, or the high-dose continuous infusion regimens used more commonly in Europe, is noted for significant toxicity.23,24 Prognostic indicators are now needed to determine which patients are more likely to respond to IL-2. Beyond the observations that patients with a Karnofsky performance status of 90 to 100 tolerated therapy better and were more likely to respond, no other pretreatment patient characteristics, including multiple laboratory studies, time from diagnosis to therapy, and involved sites, have proven to be prognostic.25 In a group of 327 patients with advanced renal cell carcinoma treated in Europe by continuous infusion of IL-2, baseline performance status, the time from diagnosis to treatment (greater or less than 24 months) and the number of metastatic sites (one versus two or more) were prognostically important.26 In a smaller group of patients treated with this same regimen, patients who continued to produce elevated serum levels of tumor necrosis factor (TNF) in the days following completion of IL-2 administration were more likely to respond.27 In renal patients who present with bulky primaries and metastatic disease and who were successfully debulked and maintained a high performance status, the response rate to IL-2 was 27%.28 Curiously, long-term progression-free intervals have been documented in a number of patients whose residual primary tumor was removed only after response of metastatic sites to IL-2 therapy.29 Therefore, several approaches for the management of these patients are being considered.

In attempts to increase the antitumor effects of IL-2, while reducing its toxicity, modifications of the original NCI regimen have been performed. However, despite a large number of published trials involving IL-2 administered in a variety of doses, schedules, and combinations with other agents and despite the difficulties in a comparative analysis of multiple small trials, it appears that none of the various approaches has led to notable increases in response rates.30 Examples include the subcutaneous administration of IL-2, noted for lower systemic levels and the less related systemic toxicities. The published experience with this approach in renal carcinoma is limited, and although it is clear that objective responses can be achieved with subcutaneous administration, the response duration and net clinical benefit have not been determined. Comparative data with the high-dose regimen is even more limited, but a preliminary analysis of the results of a randomized clinical trial with high-dose bolus IL-2 on a similar schedule using 10% of the normal dose suggests that similar response rates can be achieved.31 On the basis of promising preclinical findings, investigators have also performed studies of IL-2 combined with other cytokines in renal cell carcinoma32,33 The most studied combination is with IFN-α, in which phase II results gave little suggestion of enhanced benefit34 other than increased survival suggested in one study.35 The further addition of 5-Fluorouracil (5-FU) to the combination of IL-2 and IFN-α has in one recent report yielded a 30 to 40% response rate,36 suggesting that the combination of chemotherapy with biotherapy should be a serious consideration for future study. Optimization of cytokine combination therapy, possibly with chemotherapy, in renal carcinoma remains to be achieved.

Malignant Melanoma

IL-2 is now approved as therapy for malignant melanoma in the United States, on the basis of clear and occasional dramatic antitumor activity in this tumor.37 Several large, phase II trials using the NCI Surgery Branch high-dose regimen have been published, with 5 complete (4%) and 22 partial (16%) responses reported among 134 patients treated.15,16, 38 The addition of IFN-α to IL-2 in protocols similar to those used for renal cell carcinoma suggested the possibility of increased survival due to IFN-α, but no significant increase in response rate.39 In a recent review of these trials in melanoma performed between 1985 and 1993, it was concluded from a set of 270 patients that the response rate was 16%, and those patients who achieved complete responses are still disease free; disease did not recur in any patient who was still disease free at 30 months.40 Despite the clear activity, the relatively brief duration of many responses has led to the investigation of IL-2 administered with combination chemotherapy for melanoma to develop a therapy with greater benefit to patients.

High response rates for combination chemotherapy and immunotherapy, often called biochemotherapy, have been reported by several investigators, with most of these regimens combining cisplatin with IFN-α and IL-2. Response rates to biochemotherapy have routinely been as high as 45 to 55%, with complete response rates as high as 20%.41-45 Both the duration of these responses and the net benefit to the patients who undergo this demanding therapy are under study in ongoing in phase III clinical trials. Using a decrescendo IL-2 regimen, plus IFN-α, the addition of cisplatin was reported to double the response rate from 18 to 36% in the first European Cooperative Group phase III trial.46 Use of IL-2 as a vaccine adjuvant has also been noted, and in a direct comparison to IL-12 or Granulocyte-Monocyte Colony Stimulating Factor (GM-CSF), it was found that the vaccine of IL-2 and peptide was the only combination in which clinical responses were noted.47

Other Cancers

Additional uses for IL-2 exist in other cancers as well as nonmalignant conditions.48–52 Responses have been reported in individual patients with ovarian cancer (with both systemic and intraperitoneal cavity therapy), non–small cell lung cancer, head and neck cancer (with IL-2 administered regionally), colon cancer, breast cancer, bladder cancer (via intracavitary administration), and leptomeningeal metastases (via intraventricular injection).30,53-55 Formal phase II evaluation of IL-2 in these malignancies has been limited.

A number of reports involving the administration of IL-2, either alone or with LAK cells in patients with malignant glioma have been noted. This approach has involved surgical resection of recurrent tumor and either direct instillation of IL-2 at surgery or placement of an Ommaya reservoir to allow therapy with cytokine either alone or with IL-2–activated lymphocytes. While clinical responses have been reported, the clinical benefit of such an approach to treatment remains to be established.56 Administration of IL-2 via gene transfer for head and neck squamous cell cancer is in preliminary stages, and suggests that local IL-2 may be effective in situations where the tumors are accessible.57

Another promising clinical role for IL-2 is following high-dose chemotherapy associated with bone marrow transplantation for hematologic malignancies. Several clinical reports have been published involving the use of IL-2 in patients with relapsed acute leukemia, with objective responses reported.58,59 Further studies have suggested clinical benefits, in comparison with matched controls, for patients receiving IL-2 following high-dose therapy and bone marrow transplantation for acute myeloid leukemia in first or second relapse;60,61 it has been suggested that following bone marrow transplantation, IL-2 might amplify the graft-versus-leukemia effect and decrease the graft-versus-host effect.62 Use of bone marrow transplantation in patients with hematologic malignancies as well as breast cancer has achieved widespread practice. The use of IL-2–activated autologous lymphocytes to generate cytotoxic effector cells capable of lysing tumors, has resulted in graft-versus-host disease (GVHD) in these patients and is now found in some studies to be correlated with an antitumor effect. Through a series of clinical trials, a stable phase II dose of IL-2 has been achieved, with no deleterious effect on engraftment.63 This promising use of IL-2 is likely to be the topic of much research in the near future.

IL-2 with Adoptive Cellular Immunotherapy

Preclinical studies suggested enhanced antitumor activity when IL-2 is used together with ex vivo activated and expanded autologous lymphocytes. Also, the first objective responses with high-dose bolus IL-2 therapy were noted in patients receiving IL-2 together with LAK cells prepared through in vitro activation of autologous peripheral blood lymphocytes that were harvested by lymphopheresis, and initially, it appeared that the combination of IL-2/LAK was more active than IL-2 alone.40 Major IL-2/LAK clinical trials in patients with renal cell carcinoma have been conducted by several groups, including the NCI Surgery Branch, the IL-2/LAK Working Group, and the NCI-sponsored Modified Group C centers.15,16,20,64 A subset of the NCI Surgery Branch’s patients with renal cell carcinoma and with all patients entered into the Modified Group C trials were randomized to receive IL-2 alone or together with LAK cells. Response rates to IL-2 used alone and together with LAK cells as well as durability of responses did not differ substantially, and therefore the data do not support a major contribution of ex vivo activated and adoptively transferred LAK cells to the efficacy of high-dose bolus IL-2 in patients with renal cell carcinoma.20,65 Similar conclusions were reached regarding the adoptive transfer of LAK cells in patients with melanoma treated with high-dose bolus IL-2.15,66 It now appears that response rates with IL-2/LAK are not different from those observed with high-dose IL-2 alone, and IL-2/LAK therapy in other solid tumors has been disappointing.53,55 While attempts to generate LAK at the tumor site remain attractive, the intravenous infusion of LAK is not likely to prove effective in cases beyond the blood-borne metastatic deposits, which appear just as sensitive to the IL-2 alone.

Another disappointing use of IL-2 in cancer therapy has been shown by the clinical trials conducted with IL-2 and tumor infiltrating lymphocytes (TIL).16,67 On the basis of the theory that such lymphocytes would include those with tumor specific activity which was somehow suppressed in the vicinity of the tumor. These lymphocytes are produced by placing digested, fresh tumor biopsies into an in vitro culture with IL-2. Although some early studies have noted response rates using TIL cells together with IL-2 in the 30 to 40% range,16,67 response data with TIL cells compared with IL-2 alone do not exist; however, some patients who failed to respond to high-dose IL-2 alone have responded to their autologous TIL cells. The utility of TIL for the identification of many epitopes recognized by cytotoxic T cells on human melanoma has permitted characterization of the antigen specificities of TIL cells cultured from patients, which should prove useful in the design of vaccine strategies for the development of antigen-specific T cells. The more recent recognition of tumor specific cells from the peripheral blood of long-term responders suggests that studies of TIL may soon subside.

IL-2 Toxicities

IL-2 therapy is associated with a spectrum of cardiovascular toxicities and hemodynamic alterations that are identical to those of septic shock. This spectrum of toxicities due to IL-2 are quite different from the myelosuppression and related problems that are encountered with most chemotherapeutic agents.68 The toxicities include hypotension, which may require pressor support; a vascular leak syndrome; and respiratory insufficiency related to replacement fluid therapy in the setting of both phenomena.69,70 While the toxicities of bolus IL-2 are generally similar in melanoma and renal carcinoma patients, NCI recently reported on its 12-year experience with 1,241 patients receiving bolus infusions of IL-2, and a progressive reduction in morbidity and mortality was noted.71 While the mechanism of the vascular leak is now realized to be due to the local production of nitric oxide by endothelial cells,72 the secondary cytokines such as TNF-α generated in response to IL-2 are most likely responsible for this. In addition, confusion, renal dysfunction, hepatic dysfunction, anemia, and thrombocytopenia can all be encountered. Toxicities that are less life threatening but nevertheless may be treatment limiting include nausea, emesis, diarrhea, myalgias and arthralgias, skin erythema, and pruritus. Other less common toxicities include myocardial infarction, myocarditis, cardiac dysrhythmias, infection, renal failure, bowel infarction, and death. Death from IL-2 therapy, as high as 4% in early studies, now almost never occurs as experience in the management of the patients has been acquired. Development of second-generation IL-2 analogues that do not induce the same high levels of secondary cytokines provides promise for further reduction of the toxicities, provided that the efficacy is not dependent on these secondary effects.73 Preclinical development of IL-2 analogues is proceeding rapidly, and such molecules could be in the clinic within a few years.


Biology and Preclinical Rationale

IL-12 was originally described functionally as a natural killer stimulatory factor and cytotoxic lymphocyte maturation factor74–76 produced by monocytes. IL-12 is a heterodimeric glycoprotein of approximately 70-kd molecular weight and is composed of two unrelated glycoproteins of 40 and 35-kd, respectively, which are linked covalently by a single disulfide bond.52 The 40-kd subunit has homology with the IL-6 receptor; and the 35-kd subunit has homologies with other cytokines, particularly IL-6 and granulocyte colony-stimulating factor (GCSF).77 Therefore, the complete molecule has characteristics of both cytokine and cytokine receptor. Unique properties include a rather long plasma half-life of 6 to 7 hours compared with the several-minute half-lives of cytokines such as IL-2. The receptor for IL-12 has been described on activated T cells, NK cells, and bone marrow progenitors, thus suggesting that this agent has direct biologic effects restricted to the immune and hematopoietic systems.78,79

Functionally, IL-12 is a powerful inducer of interferon-γ from both T and NK cells.74,80,81 Induction of other cytokines such as TNF and granulocyte-macrophage colony-stimulating factors from these same cells is, however, quite limited, distinguishing it in this regard from IL-2.82,83 IL-12 is capable of enhancing NK activity, generating LAK activity, and facilitating both the proliferation and cytolytic activity of some human T lymphocytes.84,85 The depressed spontaneous NK cell activity of peripheral blood from cancer patients could be enhanced in vitro with IL-12.86

A major biologic characteristic of IL-12 is its ability to promote the differentiation of progenitor T cells into Th1 cells, which is the helper cell population distinguished by their production of IL-2 and interferon-γ. In contrast to the Th2 helper cell population, which produces the cytokines IL-4 and IL-10 and mediates the humoral immune response, the Th1 helper subset is critical in the development of inflammatory and cellular immune responses and is therefore proposed to be critical to development of the antitumor response.87 In summary, it would appear that the key immunobiologic role of IL-12 is to stimulate innate immunity through such functions as the stimulation of interferon-γ production and NK cell activity, while also promoting the development of acquired cellular immunity through the promotion of Th1 T-lymphocyte differentiation. IL-12 also has been found to have effects on the hematopoietic stem cells, enhancing myelopoiesis and supporting the growth of B-cell progenitors. While in these studies IL-12 by itself had no effects on colony formation, synergism was demonstrated when it was used in combination with stem cell factor and IL-3 in the promotion of multi-lineage hematopoietic colony formation, although the effects were less than those observed with IL-6 or IL-11.40,88

On the basis of these immunoregulatory properties, IL-12 has been studied for its potential antitumor properties. In a range of murine tumor models, IL-12 exhibited potent antitumor and antimetastatic activity.89 IL-12 had no direct effect on these tumor cells in vitro, however. In these studies, activity was dose dependent and mediated at least partly through a T-cell mechanism, with interferon-γ production also being very important to the antitumor effect.90,91 IL-12 was also demonstrated to be a potent suppressor of angiogenesis, an effect that apparently is mediated through its ability to induce interferon-γ.92,93 In these studies, the use of IL-12 with another inhibitor of angiogenesis, the fumagillin analogue TNP-470, resulted in increased antitumor efficacy. In mice receiving IL-12, a reversible dose- and time-dependent anemia, lymphopenia, and neutropenia were noted.94 Dose-limiting toxicities in early human clinical trials have included mucositis and transient, reversible, hepatotoxicity.

Clinical Applications

The central role of IL-12 in the differentiation of Th1 helper cells and the induction of IFN-α suggests that this cytokine could play an important role, either directly or in conjunction with vaccine strategies, as a therapeutic agent designed to enhance the cellular immune response against cancer cells. As noted earlier, this induction of IFN-α appears to be critical to the demonstrated antitumor as well as antimicrobial activities of IL-12. Initial clinical development strategies in cancer include the study of this agent alone in phase I trials, followed by phase II trials in renal cell carcinoma and other malignancies, and combination trials of IL-12 administered with cancer vaccines. While systemic IL-12 trials in human immunodeficiency virus (HIV)-positive patients indicated manageable toxicity, phase II trials in humans, which used different scheduling from the HIV trials, were initially halted by the FDA due to IL-12–related deaths; re-evaluation of the IL-12 biology as well as more cautious clinical trials are currently in progress.95 Recent reviews stress the need to reduce toxicity, such as via a priming dose, and also stress caution with further IL-12 studies.96 One approach which has been the local infusion of IL-12, was reviewed recently.97

Tumor Necrosis Factor-α

Biology and Preclinical Rationale

A nonglycosylated, 17-kd polypeptide, TNF-α, is expressed in both secreted and membrane-bound forms, with the secreted form circulating as a homotrimer. TNF-α binds to either of two distinct cell surface receptors of 55- and 75-kd molecular weight, respectively; these different receptor forms are independently expressed on different cell types.98 The lack of homology between the intracellular domains of these two receptor proteins suggests that they may subserve distinct cellular responses.99 Some information exists concerning these differential functions, particularly for the p55 receptor, which is important in the mediation of TNF-α–induced cytolytic activity, antiviral activity, IL-6 induction, and other biologic effects. A distinct role of the p75 receptor, beyond facilitating the binding of TNF-α to p55, was less clear until the recent observation that p75 is critical to the inflammatory skin reaction noted with TNF-α.

The cytokine studied in human clinical trials to date is TNF-β A second cytokine, termed TNF-β, or lymphotoxin, is produced by a distinct gene closely linked within the MHC on the short arm of chromosome 6; a 28% amino acid homology exists between the two cytokines.100 While activated monocytes and macrophages represent a major cellular source of TNF-β, it also is produced by activated T and NK cells and a wide variety of other cells. Depending on the cell type, TNF-β production can be stimulated by a number of signals, including lipopolysaccharide (monocytes), anti-CD3 monoclonal antibody (T cells), and other cytokines, including IL-2 (T cells). IL-4 is a potent downregulator of TNF production, similar to its effects on the production of IFN-γ and IL-6.101

Although the name tumor necrosis factor is still used for this interleukin, it merely reflects one of the first functional, in vivo effects attributed to it. In mice, it was observed that sera from (BCG)-injected mice would cause hemorrhagic necrosis of some, but not all, tumors.102 Further studies revealed that the effect was on the tumor vasculature and not on the normal vasculature, thus suggesting differences in these two vascular beds. Subsequent purification of TNF-α has led to the identification of multiple roles for the cytokine, including direct tumor cell cytotoxicity, support of the growth and proliferation of immune system cells, induction of cachexia, and amplication of the human immune system via synergy with IL-2.103–105 Induction of NO and subsequent hypotension is the dose-limiting toxicity of TNF-α in humans.106 The extreme toxicity of this agent in humans was not apparent in preclinical mouse studies; the mouse response to human TNF-α is incomplete, with recent findings indicating that at least one of the TNF-α receptors is species specific in the mouse and does not respond to human TNF-α.105,107 Therefore, other functions described in preclinical models also may be irrelevant to humans, and further research is needed for an accurate description of the clinically important responses.

Tumor necrosis factor has direct, in vitro antitumor cytotoxicity on 30 to 50% of tumor cell lines, and it has been demonstrated to be active in vivo against both murine tumors and human tumor xenografts, particularly when they have reached a size of at least 5 mm in diameter.108–112 Which of the pleiotropic biologic activities of TNF-α contributes primarily antitumor effects is unclear. Subcutaneous tumors undergo hemorrhagic necrosis after TNF-α administration, which suggests that interference with tumor neovasculature is important. Indeed, TNF-α affects endothelial cells directly, resulting in the appearance on the tumor vessel endothelial cell surface of procoagulant activity and leading to fibrin formation, leukocyte infiltration, defective perfusion, and hemorrhagic necrosis. Immunogenic tumors are most responsive to the effects of this cytokine, however, suggesting that other events are involved in the effective mechanism in animal models.111

Considerable rationale exists for the use of TNF-α with chemotherapy. In vitro, enhanced cell killing is noted when TNF-α is combined with chemotherapeutic agents that inhibit DNA topoisomerases I and II, including agents such as doxorubicin, teniposide, etoposide, and actinomycin D.88,113 The apparent mechanism involves TNF-α–mediated increases in DNA strand breakage. This enhanced effect also was observed in preclinical in vivo models, where enhanced antitumor activity was observed when TNF-α was combined with doxorubicin or etoposide.114,115

Clinical Applications

Systemic Therapy

On the basis of preclinical information described earlier, a series of phase I and II clinical trials were performed involving the systemic administration of TNF-α. Recently reviewed116 results indicate severe toxicity due to pleiotripic effects on immunocompetent cells. The maximum tolerated dose (MTD) of bolus TNF-α in patients has consistently been in the range of 200 to 400 mg/m2, 5- to 10-fold lower than the doses achievable in rodents that were active against tumors. The single-dose MTD was quite similar, regardless of whether TNF-α was administered as a single dose, three times weekly, or 5 days a week. Shortly after TNF-α infusion, rigors, hypertension, and tachycardia develop, followed within 1 to 2 hours by fever and several hours later by hypotension. The dose-limiting toxicity has consistently been hypotension, which responds to therapy with fluid and vasopressors, although patients also develop a variety of constitutional symptoms. In studies where continuous infusion TNF-α has been administered, side effects of reversible thrombocytopenia, leukopenia, and hepatotoxicity, in addition to constitutional symptoms, including fatigue, malaise, diarrhea, headache, and confusion, have been observed.

Minimal antitumor activity was observed in patients who were treated with systemically administered TNF-α, either in the phase I studies or in a series of phase II trials performed across the spectrum of common solid tumors, including renal cell carcinoma, melanoma, sarcomas, and adenocarcinomas of the colon, stomach, and pancreas. Phase I clinical trials involving TNF-α in combination with either chemotherapeutic agents or other biologic agents have also been conducted. Several clinical trials of TNF-α combined with IL-2 have been conducted on the basis of compelling preclinical evidence for synergy, particularly when TNF-α was administered before IL-2.117,118 These trials show no evidence of an increased clinical benefit to the combination but do show evidence of an increased toxicity when TNF-α is administered either together with or following IL-2, which is not surprising given that IL-2 is a powerful inducer of TNF-α in patients.8,9,11,119 Similarly, despite some preclinical data suggesting an interaction, no apparent clinical benefit, or increased immunologic stimulation has been observed in clinical trials of TNF-α combined with interferon-γ64,109,120,121

To date, results with TNF-α used together with chemotherapy have also been disappointing, given the impressive evidence from in vitro and animal studies. Myelosuppression was dose limiting when using a combination of TNF-α and etoposide.122 In a randomized, phase II trial of carmustine (BCNU) administered either alone or with TNF-α, no apparent benefit but increased toxicity, was observed with the combination.123

One explanation for the discrepant results between the antitumor activity observed in rodent models and human trials involving TNF-α alone or in combination is the large difference in the tolerability of systemic doses of human TNF-α between different species and the fact that only limited systemic doses of TNF-α (considerably lower than the active doses in rodents) can be administered safely to patients. As noted later, the development of isolation-perfusion limb therapy with TNF-α has allowed exploration of therapeutic activity of levels of the cytokine similar to those that are achievable in preclinical models.124

The role of TNF-α as well as other cytokines, such as IL-1 and IL-6 in the wasting syndrome or cachexia which is observed in many patients with cancer, has been investigated.125 Because many patients with cancer have elevated plasma TNF-α levels, therapeutic strategies to decrease TNF-α production have been developed in an attempt to interrupt this wasting syndrome. One such strategy involves the administration of pentoxifylline, which lowers TNF-α expression at both the RNA and protein levels.126 Another proposed method for regulation is administration of either megestrol acetate or medroxyprogesterone acetate for which clinical trials are beginning.127 In preliminary studies, lowered TNF-α levels, associated with an improved sense of well-being and improved appetite, were observed.128

Regional Perfusion Therapy

The paradox between the remarkable antitumor activity of high-dose TNF-α in animal systems and its lack of clinical utility when administered systemically at tolerable doses in humans has led to extensive clinical study of TNF-α administered loco-regionally124,129–132 TNF-α has been administered intratumorally, intraperitoneally, and by intravesical or intra-arterial infusion. The most interesting and clinically beneficial results, however, have followed isolated limb perfusion of TNF-α together with melphalan, IFN-γ, and hyperthermia in patients with regionally recurrent melanoma or primary limb sarcomas. This strategy allows the achievement of high peak TNF-α concentrations, while greatly limiting systemic exposure. One complete response was noted among three patients treated using isolated limb perfusion with TNF-α alone;133 all other patients have been treated with one or another variant of the biologic-chemotherapeutic combination therapy. The origin of the combination infusion approach with melphalan, interferon-γ, and hyperthermia was the demonstrated synergy between TNF-α and each of these agents or modalities.109,134 Systemic leakage is monitored continuously during the perfusion procedure by using radioactive serum albumin and a gamma detector placed above the heart.135 Clinical results using this approach are dramatic, with objective response rates of 100% in patients with regional extremity melanoma metastases and complete response rates in several studies exceeding 70%. Systemic toxicities are minimal, with hypotension managed by fluid supplement and administration of vasoactive amines. Regional toxicities appear to be similar to those observed with hyperthermic melphalan perfusion alone. Responses appear to be durable, and although this locoregional approach in melanoma in unlikely to affect median survival, the palliative effects can be significant in individual patients. Angiographic and immunohistologic studies show rapid elimination of tumor hypervascularization and endothelial cell destruction, suggesting that the interruption of tumor blood supply is an important mechanism of this approach, which is consistent with the biologic properties of TNF-α.136 Randomized trials in Europe and the United States are examining the relative contributions of each biologic constituent to the baseline activity observed with melphalan and hyperthermia alone. Similar regional treatment strategies are being attempted in isolated lung and liver perfusions.137


Biology and Preclinical Rationale

IL-1 is a cytokine with diverse immunologic, physiologic, and hematopoietic effects, produced mainly by macrophages and monocytes. Two forms of IL-1 (α and β exist. Although these two glycoproteins of 17-kd molecular weight are distinct gene products and despite only a 26% homology, they bind to the same receptors and have similar biologic activities.103,104,138 IL-1 appears to be primarily involved in inflammation, having direct effects on endothelial cells as well as on both B and T cells. Through induction of other cytokines, including TNF-α, a cascade of biologic events are affected by IL-1. This cytokine has direct antitumor activity both in vitro and in vivo, and the in vivo effects are characterized by acute hemorrhagic necrosis associated with microvascular injury, decreased tumor bloodflow, and significant clonogenic tumor cell kill.139

Interleukin-1 also has a number of effects on the hematopoietic system, inducing the stimulation of bone marrow stromal cells to produce IL-6 in addition to a range of colony-stimulating factors.140–42 Furthermore, IL-1 synergizes with these colony-stimulating factors in vitro to promote the differentiation and proliferation of hematopoietic progenitor cells, is myeloprotective if administered before radiation or chemotherapy in preclinical studies, and can accelerate the recovery of both neutrophils and platelets after chemotherapy or sublethal radiation.143–147

Additionally, the use of IL-1 with chemotherapy has resulted in improved antitumor efficacy through a variety of possible mechanisms, which include chemotherapy-induced upregulation of IL-1 receptors on the surface of tumor cells and IL-1–induced alterations in tumor bloodflow.148,149 The diverse mechanisms by which IL-1 may exert a beneficial antitumor effect—including through direct cytotoxicity, induction of tumor hemorrhagic necrosis, activation of immune effector cells, and enhancement of chemotherapy effect together with attenuation of chemotherapy-induced hematopoietic effects—have made it an attractive candidate for clinical trials in patients with cancer.

Clinical Trials

Interleukin-1 also has been studied for its myelorestorative functions. Platelet counts increased 1 to 2 weeks following therapy with IL-1 in the phase I trials of both IL-1β_ and IL-1α, in association with increases in bone marrow megakaryocytes and serum levels of the thrombopoietin IL-6. In clinical trials, IL-1 was shown to accelerate the recovery of platelets and to shorten the duration of carboplatin-induced thrombocytopenia.150 A published review of the IL-1 trials concludes that IL-1 alone has little antitumor activity when tested for efficacy with many types of malignancies, and that the dose-related toxicity can be severe yet manageable. As IL-1 appeared to increase the responsiveness of immune progenitor cells to other hematopoietic cytokines such as IL-3 or CSF, one potential application is to expand cells prior to escalation of chemotherapies.151


Biology and Preclinical Rationale

Interleukin-6, as well as IL-3 and IL-11, are important regulatory proteins for hematopoiesis, and their greatest relevance to clinical oncology probably relates to their use as growth factors for chemotherapy-associated myelosuppression, as discussed in other chapters. In addition to its properties as a thrombopoietin, however, IL-6 has a wide variety of biologic effects, which have led to its use in cancer treatment.152–154 IL-6 is produced by a range of cells, including T cells, monocytes and macrophages, fibroblasts, keratinocytes, and endothelial cells, and its variety of biologic effects led to its initial, independent characterizations as a B-cell growth factor and T-cell differentiation factor, a plasmacytoma growth factor, and a hepatocyte-stimulating factor.155-160 IL-6 is a 21- to 30-kd glycoprotein of 212 amino acids that binds to a specific receptor that requires the same 130-kd membrane glycoprotein for mediation of signal transduction, as has been described for several cytokines, including IL-2.161,162 The biologic effects of IL-6 include those on the synthesis of acute phase reactants in the liver, on the hypothalamic-pituitary axis, on bone resorption, and on both the humoral and cellular arms of the immune system.157,163–166 As a major inducer of the acute phase response, the cytokine may play a role in the pathogenesis of sepsis.

Clinical Trials

Phase I trials of both intravenous and subcutaneous IL-6 have been conducted in patients with advanced cancer.167,168 All patients experienced constitutional symptoms, including fever, chills, and fatigue. Significant increases in cross-reactive protein, fibrinogen, platelet counts, and soluble lymphocyte IL-2 receptor levels were observed at doses greater than 3 mg/kg. These increases in inflammation-associated proteins were accompanied by a fall both in serum albumin and hemoglobin levels. In general, the cytokine was well tolerated, although both hyperbilirubinemia and atrial fibrillation were observed at 10 mg/kg. In a phase II trial of IL-6 in advanced renal cell cancer patients, no alterations in the presence of blood cell subsets or induction of secondary cytokines was observed, although evidence of T-cell activation was noted as indicated by the increased serum levels of sCD25; soluble TNF-α receptors were also noted as was the expected rise in acute phase proteins.169


Biology and Preclinical Rationale

Interleukin-4 is the product of a subset of activated T helper cells and was originally characterized by its ability to stimulate the proliferation of activated B cells. IL-4 has been reported to exhibit many other biologic activities as well, including induction of class II MHC expression on B cells, regulation of immunoglobin E (IgE) and IgG1 secretion, as well as the expression of specific receptors of IgE. In addition to B-cell regulation, IL-4 possesses the ability to directly stimulate as well as inhibit various subclasses of T cells. Additional reports indicate that IL-4 activates the connective-tissue-type mast cells. The various functions of IL-4 are not resolved, but its apparent ability to inhibit lymphocyte response to IL-2 while promoting antigen-specific interactions may prove to be applicable to tumor regulation, especially in melanoma, where tumor-specific, tumor-infiltrating lymphocytes are reported to maintain tumor specificity in response to IL-4 and lose specificity when cultured in IL-2.

Human IL-4 is expressed in a single form, as evidenced by one major peak of activity on immunoelectrophoresis gels.164 The apparent molecular weight is 12 to 15 kd as determined by sodium dodecil sultate (SDS)-polyacrylamide gel electropheresis. Similar to IL-2, the one interchain disulfide bond is required for biologic activity. IL-4 apparently exerts its biologic activity through a single class of high-affinity receptors found on both hematopoietic and nonhematopoietic lineage cells. IL-4 receptor-positive cells include resting T and B cells, macrophages, myeloid progenitors, stromal cells, fibroblasts, and liver cells. In addition to potentiating antigen-specific immune responses, potential clinical applications are suggested by its anti-inflammatory effects.170

IL-4 is a pleiotropic B- and T-cell growth and differentiation factor. Unlike IL-2, but similar to TNF-α, it is species specific, and the differences between the immunologic activities of murine and human IL-4 as well as the absence of predictive tumor models for human IL-4 have made the preclinical study of recombinant human IL-4 difficult. Because IL-4 can augment antigen-specific cytolytic T cells and induce differentiation of human B lymphocytes, including some leukemic B lymphocytes, clinical trials have been initiated to assess its clinical activity in patients with solid and hematologic malignancies.

Clinical Trials

A series of phase I and II clinical trials have been conducted with recombinant IL-4 administered by both the subcutaneous and intravenous routes.171–173 At higher doses, side effects that have been associated with cytokine treatment include diarrhea, gastric ulceration, headache with nasal congestion, fluid retention, and arthralgia, in addition to constitutional symptoms such as fatigue, anorexia, nausea, and vomiting. Interestingly, intravenous IL-4 therapy was associated with no increase in TNF-α levels, and the observed increase in the levels of IL-1 receptor antagonist (in contrast to IL-2 therapy) is consistent with predictions from the preclinical studies.171 A detailed summary of the safety evaluation has been published174 Multi-institutional, phase II trials of intravenously administered IL-4 were conducted in both renal cell carcinoma and melanoma, with only a single response, in a patient with melanoma,175 and in non–small cell carcinoma, prolonged disease stabilization and low toxicity appeared promising.176

Colony-Stimulating Factors

Macrophage colony-stimulating factor (M-CSF) is a bone marrow derived glycoprotein that is capable of supporting the proliferation, maturation, and activation of cells of the mononuclear phagocyte lineage177,178 and has been approved for therapy already in Japan. M-CSF binds to a specific, high-affinity tissue receptor that is expressed on monocytes and macrophages and is encoded by the c-fms oncogene.179 M-CSF–activated monocytes and macrophages have enhanced in vitro tumoricidal and antimicrobial activities, which form the basis of the interest in this agent for both its potential anticancer and antiinfectious properties.180–183 M-CSF has antitumor activity in preclinical studies, with reduced number of metastases and prolonged survival noted in B16 melanoma, although apparently greater activity was observed when the cytokine was used in therapy with an antitumor monoclonal antibody.184,185 G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte macrophage colony-stimulating factor) are stimulating factors for the cells in their names, with G-CSF showing efficacy and GM-CSF showing broader functional activity in early trials; a comparative analysis of these CSFs was recently reported.186

Significant biologic and clinical effects have been observed with two different recombinant M-CSFs as well as with a urine-derived human M-CSF studied in Japan, with relatively little toxicity except at the very highest doses.155,187–190 Dose- and schedule-dependent monocytosis were observed and associated with reciprocal changes in the peripheral blood platelet count.187 Decreases in serum cholesterol and low-density lipoproteins, similar to observations made in preclinical studies, also were observed as well as clinical responses in patients with melanoma, renal cell carcinoma, and leiomyosarcoma were observed. Potential uses for the various CSFs in clinical oncology include administration with monoclonal antitumor antibodies or other cytokines in cancer therapy or following bone marrow transplantation, where monocyte-activating properties might be useful for both antitumor and antifungal effects.191,192


Interleukin-10 is an important immunoregulatory cytokine, whose principal biologic function appears to involve the suppression of the cytokine synthesis in the Th1 subset of CD4 1 T helper cells. Originally described as cytokine synthesis inhibitory factor, this 35-kd noncovalently linked homodimeric peptide is produced by both Th1 and Th2 T cells, monocytes, B lymphocytes, and keratinocytes.193,194 The suppression by IL-10 of IL-2 and interferon-γ production by Th1 CD4 1 cells and of IL-1, TNF-α, IL-6, IL-8, and colony-stimulating factors by monocytes, coupled with its ability to stimulate B-cell growth and immunoglobulin production suggests that IL-10 could find a therapeutic use in sepsis and a number of autoimmune diseases that are associated with inflammation. Indeed, therapy with this cytokine in animal models of sepsis results in improved survival.135,195,196 The suppressive effects of IL-10 on cell-mediated immunity suggest that it might find a role in transplant rejection or the treatment of GVHD.197 In two phase I trials of single bolus, intravenous doses of recombinant IL-10 administered to normal volunteers, no adverse side effects were noted, and a transient neutrophilia and monocytosis associated with significant lymphopenia, inhibition of T-cell proliferation, and dose-dependent inhibition of TNF-α and IL-1-β production were also noted.198,199 IL-10 is expected to have great utility in the regulation of autoimmune disease, for which suppression of the T helper cell activity is desired.


Like IL-4 and IL-10, IL-13 is another cytokine produced by activated T cells; it shares the capacity to inhibit cytokine synthesis by activated monocytes and modulates B-cell responses through its effects on the activation, proliferation, and differentiation of B cells.200,201


Interleukin-15 is a recently defined, novel cytokine that, despite having no sequence homology with IL-2, binds with the β and γ components of the IL-2 receptor.202,203 IL-15 is expressed in a much wider range of tissues than IL-2, including activated monocytes and macrophages and skeletal muscle, kidney, and placenta. Similar to IL-2, IL-15 has been demonstrated to potentiate NK-cell cytokine production and cytotoxic activity; together with its production by monocytes and macrophages, these observations suggest that it may play a role in normal host immunity.204,205 Potential uses for IL-15 in cancer therapeutics are still being considered.


Much has been learned after more than a decade of clinical investigation involving recombinant cytokines. IL-2 has already become a standard approved therapy for renal cell carcinoma as well as melanoma, and investigations into the improvement of this approach as well as application to other cancers is in progress. For other cytokines, clinical studies have proceeded in parallel with basic investigations concerning the biology of these regulatory proteins and their interactions with the spectrum of lymphoid-effector cells; in many cases, clinical observations have led to further preclinical study. Despite the wide clinical experience with these agents and the optimistic predictions from the preclinical studies, defined areas of meaningful therapeutic utility for these agents still remain modest. Seeking an explanation for this apparent discrepancy is a valid exercise. One apparent possibility is that, while useful in defining biologic mechanisms and establishing general principles related to dose, schedule, and other variables, the preclinical models do not define the immunobiologic heterogeneity of the patient populations under treatment. In notable cases, it is now appreciated that the pattern of cytokine response in murine models does not parallel that observed in humans. In contrast to the contrived homogeneity of preclinical models, which often use tumor cell lines in homozygous animal systems, the biologically heterogeneous tumors developing in a genetically diverse patient population challenge attempts to dissect the value of a single therapeutic manipulation during an individual trial. Determination of simple response rates in the setting of the limited numbers of biologically dissimilar patients entered into the classic phase II trial may not provide an accurate test of therapeutic hypotheses. It would seem, therefore, that more rapid therapeutic advances will follow our improved ability to define the biology of the tumors and of the patients under therapy and correlation with clinical outcome. Emerging information concerning the heterogeneous endogenous cytokine expression of tumors is indicating possible biologic subclasses within identical histologic types of cancers. Better characterization of groups of patients, including genetic potential for cytokine responsiveness by individual immune systems will lead to an improved therapeutic benefit ratio for individual patients and greater efficiency in the conduct of clinical trials.


Much appreciation is expressed to David Parkinson, MD, co-author of the “Cytokines” chapter in the earlier edition of this text, and whose help with and insight into the original version were extremely valuable.


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