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Published on: June 28, 2021
Pharmacologic administration of interleukin-2
Antonio Romo de Vivar Chavez1, William Buchser, Per H Basse
1University of Pittsburgh Cancer Institute, Pennsylvania, USA.
Abstract:
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.
Insights
Interleukin 2 (IL-2) cancer therapy shows durable responses but causes toxicity. This study proposes IL-2
Area of Science:
- Immunology and Cancer Therapy
- Molecular Biology and Cellular Mechanisms
Background:
- Biologic therapies for cancer face challenges due to complex biological feedback mechanisms.
- Recombinant interleukin 2 (IL-2), a T-cell growth factor, was approved in 1984 and regulates effector and regulatory T cells.
- IL-2 therapy yields durable complete responses in 5-10% of melanoma and renal cell carcinoma patients, but is limited by manageable toxicities.
Purpose of the Study:
- To explore the underlying mechanisms of IL-2 therapy's systemic toxicity.
- To investigate the potential role of autophagy in IL-2-induced side effects.
- To consider the therapeutic potential and challenges of using autophagy inhibitors with IL-2.
Main Methods:
- The study proposes a novel hypothesis based on existing knowledge of IL-2 therapy and cellular processes.
- It considers the systemic syndrome associated with IL-2 administration.
- The potential role of autophagy inhibitors is explored theoretically.
Main Results:
- The proposed mechanism suggests IL-2 toxicity is linked to global cytokine-induced autophagy and temporary tissue dysfunction.
- This provides a new framework for understanding IL-2's side effects.
- The study does not present new experimental data but offers a theoretical model.
Conclusions:
- Systemic toxicity from IL-2 therapy may be driven by cytokine-induced autophagy.
- Autophagy inhibitors could potentially enhance IL-2 efficacy and reduce toxicity.
- Further research is needed to validate this hypothesis and assess the feasibility of using autophagy inhibitors.
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