The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses (original) (raw)
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Prospects of IL-2 in Cancer Immunotherapy
BioMed research international, 2018
IL-2 is a powerful immune growth factor and it plays important role in sustaining T cell response. The potential of IL-2 in expanding T cells without loss of functionality has led to its early use in cancer immunotherapy. IL-2 has been reported to induce complete and durable regressions in cancer patients but immune related adverse effects have been reported (irAE). The present review discusses the prospects of IL-2 in immunotherapy for cancer.
Interleukin-2 and cancer: Critical analysis of results, problems and expectations
The cancer process is a combination of two kind of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.
Human Interleukin 2 (IL-2) Promotion of Immune Regulation and ClinicalOutcomes: A Review
Journal of Cytokine Biology, 2016
Interleukin 2 (IL-2) is a monomeric glycoprotein that is primarily produced by activated CD4+ T cells, CD8+ T cells and dendritic cells. It is characterized as a proinflammatory cytokine that is secreted by Th1 cells. IL-2 plays a central role in the activation of regulatory T cells to produce the cytokines tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). IL-2 may also enhance the cytolytic activity of natural killer cells, thereby ensuring their significance in the control of the immune response, and effectively participate in the pathogenesis of several pathological conditions, such as cancer and metabolic, infectious, autoimmune and inflammatory diseases. We emphasize the importance of studies of IL-2 and discuss perspectives resulting from our increasing understanding of genetic diversity and its role in the immune response.
Rethinking Oncologic Treatment Strategies with Interleukin-2
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High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, the adoption of high-dose rhIL-2 has been restricted by its severe treatment-related adverse event (TRAE) profile, which necessitates highly experienced clinical providers familiar with rhIL-2 administration and readily accessible critical care medicine support. Given the comparatively wide-ranging successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies, there have been concerted efforts to significantly improve the efficacy and toxicities of IL-2-based immunotherapeutic approaches. In this review, we highlight novel drug development strategies, including biochemical modifications and engineered IL-2 variants, to expand the nar...
Forecasting the cytokine storm following systemic interleukin (IL)-2 administration
Journal of translational medicine, 2004
Extensive clinical experience has shown that systemic interleukin (IL)-2 administration can induce complete or partial regression of renal cell cancer (RCC) metastases in 15 to 20 % of patients. Since IL-2 has no direct anti-cancer effects, it is believed that cancer regression is mediated either by a direct modulation of immune cell effector functions or through the mediation of soluble factors released as a result of IL-2 administration.We previously observed that transcriptional and protein changes induced by systemic IL-2 administration affect predominantly mononuclear phagocytes with little effect, particularly within the tumor microenvironment, on T cell activation, localization and proliferation. It further appeared that mononuclear phagocyte activation could be best explained by the indirect mediation of a secondary release of cytokines by IL-2 responsive cells either in the circulation or in peripheral tissues.To better characterize the cytokine outburst that follows system...
Medical Hypotheses, 2003
The cancer process is a combination of two kind of events: a multistep cellular genetic defects giving cells independent growth and great adaptation capability, a multistep interactions profiles with what is called the stromal reaction from the original in situ tumor to the invasive metastatic and angiogenic tumor. The immune system plays an important role in the control of the cancer process but always must be seen as a part integrated in the stromal reaction. In order to boost the immune system capability to treat a cancer we must never forget these cellular and tissular dimensions. Interleukins, growth factors and monoclonal antibodies are new agents are able to bring immunotherapy of cancer to reality. Interleukin 2 did not match our dreams of the ideal factor which can stimulate the defective immune system and bring the cancer evolution to an end. The little but real remissions obtained with the IL-2 high dose protocols still sustains our trust of the immune system as a critical barrier to cancer evolution but the numerous side effects reminds us that cytokines are not to be used as antibiotics and hormones. IL-2 is a regulator of the immune system at the microenvironment level, therefore flooding the blood circulation with high IL-2 doses is not appropriate. We have also to understand that IL-2 can interact directly with cancer cells and also with stromal cells (endothelial and fibroblastic cells), the outcome of IL-2 immunotherapy is not restricted to the interactions with immune cells.
Cancer Research
The availability of recombinant human interleukin 2 (rl I IL 2) has resulted in its clinical utilization both as a single agent and in combination with lymphokine-activated killer cells. In this report, we discuss the effects of rH IL 2, administered by various routes, on effector cell function, pharmacokinetics and bioavailability, and therapeutic activity. Studies of the pharmacokinetics of in vitro natural killer (NK) cell augmentation by rH IL 2 revealed that a short exposure to high levels of rH IL 2 can augment NK cell activity; however, a prolonged exposure (>12 h) was required to augment NK cell activity at lower doses of rH IL 2. These observations suggested that chronic administration of rH IL 2 might improve immunomodulatory and therapeutic activity. This hy pothesis was supported by the results of studies in which we treated experimental and spontaneous metastasis, which revealed that the daily i.p. administration of rH IL 2 resulted in significantly greater therapeutic activity than administration three times/week. The therapeutic protocol for daily i.p. administration had a biphasic dosage optimum, such that low dose therapeutic activity was observed at approximately 100-1000 units/animal in the treatment of experimental métastasesor 10 to 100 units/animal in the treatment of spontaneous métastases. There was a second dosage optimum at > 100,000 units/animal rH IL 2 delivered i.p. on a daily basis. Intermediate doses had no significant therapeutic activ ity. Additional studies revealed that low dose therapeutic activity was not observed in nude mice. In contrast, therapeutic activity was observed in nude mice at high doses of rH IL 2 suggesting that low dose activity was associated with a T-cell-mediated effect, whereas high dose activity may have been mediated by NK or lymphokine-activated killer-like cells. This observation was in agreement with the dose response for T-cell adjuvant activity supporting the hypothesis that low dose therapeutic activity was T-cell associated, because adjuvant activity was observed when rH IL 2 was given daily at approximately 100 units/animal for 3 days, and higher doses had no activity or had a suppressive effect. Because we were concerned about the pharmacological aspects of rH IL 2 treatment, we also examined its therapeutic properties after continuous administration i.p. by osmotic pumps. Under these conditions, therapeutic activity was observed after administration of 600 units/h, whereas lower or higher doses did not have significant therapeutic activity.
Pharmacologic Administration of Interleukin-2
Annals of the New York Academy of Sciences, 2009
The development of biologic therapies for patients with cancer has in part been impeded by the extraordinary complexity and intrinsic feedback mechanisms promoting homeostasis in tissue injury, repair, inflammation, and immunity. Recombinant interleukin 2 (IL-2) therapy was initiated in 1984 based on its role as the prototypic T-cell growth factor, with novel roles deduced late after its FDA approval in regulating not only effector T cells but also regulatory T cells. Complicating its application, even in the most sophisticated centers, has been the manageable but difficult toxicities attendant on its use in spite of clear evidence of complete responses in 5-10% of treated patients with melanoma and renal cell carcinoma with extraordinary durability lasting now for almost 25 years, thus tantamount to "cures." Although efforts have been made to diminish toxicity or enhance efficacy the only substantive advance in combination therapy has been the application of tumor-infiltrating lymphocytes and the antibody to CTLA4. A deeper understanding of the "limiting" toxicity associated with mild flu-like symptoms and more debilitating cytokine "storm" not forthcoming. Here we propose the notion that the systemic syndrome associated with IL-2 administration is due to global cytokine-induced autophagy and temporally limited tissue dysfunction. The possible role of autophagy inhibitors to enhance efficacy and limit toxicity as well as possible problems with this approach are considered.
Cancer Research, 1987
The availability of recombinant human interleukin 2 (rl I IL 2) has resulted in its clinical utilization both as a single agent and in combination with lymphokine-activated killer cells. In this report, we discuss the effects of rH IL 2, administered by various routes, on effector cell function, pharmacokinetics and bioavailability, and therapeutic activity. Studies of the pharmacokinetics of in vitro natural killer (NK) cell augmentation by rH IL 2 revealed that a short exposure to high levels of rH IL 2 can augment NK cell activity; however, a prolonged exposure (>12 h) was required to augment NK cell activity at lower doses of rH IL 2. These observations suggested that chronic administration of rH IL 2 might improve immunomodulatory and therapeutic activity. This hy pothesis was supported by the results of studies in which we treated experimental and spontaneous metastasis, which revealed that the daily i.p. administration of rH IL 2 resulted in significantly greater therapeutic activity than administration three times/week. The therapeutic protocol for daily i.p. administration had a biphasic dosage optimum, such that low dose therapeutic activity was observed at approximately 100-1000 units/animal in the treatment of experimental métastasesor 10 to 100 units/animal in the treatment of spontaneous métastases. There was a second dosage optimum at > 100,000 units/animal rH IL 2 delivered i.p. on a daily basis. Intermediate doses had no significant therapeutic activ ity. Additional studies revealed that low dose therapeutic activity was not observed in nude mice. In contrast, therapeutic activity was observed in nude mice at high doses of rH IL 2 suggesting that low dose activity was associated with a T-cell-mediated effect, whereas high dose activity may have been mediated by NK or lymphokine-activated killer-like cells. This observation was in agreement with the dose response for T-cell adjuvant activity supporting the hypothesis that low dose therapeutic activity was T-cell associated, because adjuvant activity was observed when rH IL 2 was given daily at approximately 100 units/animal for 3 days, and higher doses had no activity or had a suppressive effect. Because we were concerned about the pharmacological aspects of rH IL 2 treatment, we also examined its therapeutic properties after continuous administration i.p. by osmotic pumps. Under these conditions, therapeutic activity was observed after administration of 600 units/h, whereas lower or higher doses did not have significant therapeutic activity.