The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses

Abstract

BackgroundThis year marks the twentieth anniversary of the approval by the US Food and Drug Administration of interleukin-2 (IL2) for use in cancer therapy, initially for renal cell carcinoma and later for melanoma. IL2 therapy for cancer has stood the test of time, with continued widespread use in Europe, parts of Asia, and the US. Clinical complete responses are variably reported at 5%–20% for advanced malignant melanoma and renal cell carcinoma, with strong durable responses and sustained long-term 5–10-year survival being typical if complete responses are generated.MethodsThe literature was reviewed for the actions and clinical effects of IL2 on subsets of T cells. The influence of IL2 on clinical efficacy was also sought.ResultsThe review revealed that IL2 is capable of stimulating different populations of T cells in humans to induce either T effector or T regulatory responses. This apparent “functional paradox” has confounded a clear understanding of the mechanisms behind the clinical effects that are observed during and following administration of IL2 therapy. An average complete response rate of around 7% in small and large clinical trials using IL2 for advanced renal cell carcinoma and malignant melanoma has been shown from a recent review of the literature.ConclusionThis review considers the published literature concerning the actions and emerging clinical effects of IL2 therapy, spanning its 20-year period in clinical use. It further details some of the recently described “bimodal” effects of IL2 to explain the apparent functional paradox, and how IL2 might be harnessed to emerge rapidly as a much more effective and predictable clinical agent in the near future.

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

“…The authors agree that peri-treatment mortality can be reduced to less than 1% when guidelines are diligently followed. High priority research includes an exploration of combination therapy wherein IL-2 is used with other immunotherapy agents, stereotactic radiation, or new targeted therapeutics being developed for these diseases [44,59]. Another high priority is the identification and validation of predictive biomarkers to better select potential responders prior to treatment.…”

Truncated Escherichia coli thioredoxin induces proliferation of human blood mononuclear cells and production of reactive oxygen species as well as proinflammatory cytokines

“…Immunostimulatory drugs have been exploited for treating cancers such as superficial bladder cancer, renal cancer and melanoma. [28][29][30] Ex vivo expansion/activation of antitumor lymphocytes followed by reinfusion into patients was discovered to be a new therapeutic modality. 31,32 Substances that can trigger immune responses are in demand for further development of immunotherapy.…”

Production of recombinant immunotherapeutics for anticancer treatment

“…Interleukin-2 plays a role in activating the production and stimulating the expansion of T cells 8 and has indications for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Although this recombinant cytokine presents low complete response rates of approximately 15%, 5 the response is durable (approximately 10 y) in that specific group of patients.…”

“…Although this recombinant cytokine presents low complete response rates of approximately 15%, 5 the response is durable (approximately 10 y) in that specific group of patients. 8 Furthermore, there is a significant risk of systemic inflammation that requires interleukin-2 administration to be an inpatient procedure.…”