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Review
. 2025 May 30;13(5):e011119.
doi: 10.1136/jitc-2024-011119.

Role of high-dose interleukin-2 for melanoma in the age of cellular therapy

Elizabeth Buchbinder  1 , Michael T Lotze  2 , Kim A Margolin  3 , Rodabe Amaria  4 , Amod Sarnaik  5 , Virginia Seery  6 , Zeynep Eroglu  7 , Karam Khaddour  8 , Allison Betof Warner  9 , Harriet M Kluger  10 , Mario Sznol  11 , Michael B Atkins  12 , David F Mcdermott  6 , Ann W Silk  13
Affiliations
Review

Role of high-dose interleukin-2 for melanoma in the age of cellular therapy

Elizabeth Buchbinder et al. J Immunother Cancer. .

Abstract

Interleukin-2 (IL-2) was one of the first immunotherapies in the treatment of patients with cancer. High-dose bolus IL-2 (HD IL-2) can induce durable complete or partial tumor regression in a small proportion of advanced melanoma and renal cell carcinoma patients. However, its potential for life-threatening side effects and requirement for inpatient administration limits its use to patients with excellent organ function treated at experienced centers. In 2024, following decades of foundational work at the National Cancer Institute, lifileucel became the first FDA-approved tumor-infiltrating lymphocyte (TIL) therapy for cancer. HD IL-2 is routinely given after TIL infusion to promote the survival and proliferation of the T cell product. In this context, fewer doses are given, and the parameters for holding an IL-2 dose are more conservative, as compared with HD IL-2 monotherapy, which has now fallen out of routine use. The lower number of doses, and possibly the effects of the preparative lymphodepletion, result in much less cytokine-related toxicity. Nevertheless, concerns related to HD IL-2 toxicity persist and possibly impact decisions to offer TIL when indicated. Here, we discuss the differences in the administration of HD IL-2 as a monotherapy vs an adjunctive therapy following TIL infusion, in an effort to demystify the toxicity of HD IL-2 in the era of cellular therapy.

Keywords: Cytokine; Tumor infiltrating lymphocyte - TIL.

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Conflict of interest statement

Competing interests: EB consults as an advisory board member for Werewolf pharma, Merck, Anaveon, Obsidian and Zola, receives clinical trial support from Genentech. MTL consults as an advisory board member for ZaiLabs, Mural, BioCept, iRepertoire, Zola Therapeutics, AppelSauce. KAM consults for Werewolf pharma, Tallac, Pfizer, Merck, ImadinAb, Daiichi-Sankyo, BMS, Astra-Zeneca, Beigene, T-Nanobio, Iovance and Elicio, receives clinical trial support from Agenus, Immunocore, and Regeneron. RNA consults as an advisory board member for Erasca, Replimmune, Obsidian, KSQ, IO Biotech, receives research funding from Obsidian, Immatics, KSQ, Regeneron, Erasca, OnKure, Roche. AS consulted for Blueprint Oncology Concepts, Gerson Lehrman Group, Guidepoint, Second City Sciences, and Iovance Biotherapeutics, has received research funding support from Iovance Biotherapeutics, Provectus Biopharmaceuticals and Turnstone Biologics, and whose institution has licensed intellectual property to Iovance Biotherapeutics. HMK receives consulting fees from Iovance, Merck, Chemocentryx, BMS, Signatera, Gigagen, GI reviewers, Pliant Therapeutics, Eisai, Invox, Wereworf pharma, Teva, Replimune and Genmab, receives clinical trial support from Merck, BMS, Apexigen and Pfizer. MS has Stock and stock options: Actym (stock options only), Adaptive Biotechnologies (stock options only), Asher Bio, Evolveimmune, Glaxo-Smith Kline (stock), Intensity (stock options only), Johnson and Johnson (stock), Nextcure, Normunity, Oncohost, Rootpath, Thetis, receives consulting fees from iTeos, Regeneron, Simcha, Nextcure, Biond (DSMC), Normunity, Cullinan, Bristol-Myers, Ideaya (DSMC), Turnstone, Evolveimmune, Dynamicure, Biontech (DSMC), Teva, Innate pharma, Nimbus, Pathios, Asher, Xilio, GI Innovation, IO Biotech, Immatics, Bioinvent, Lyvgen, Sanofi (DSMC), Pfizer, Incyte, Anaptys, Pliant, Iovance, Molecular Partners, Sumitomo, Numab, Alligator, Partner Therapeutics, Oncohost, Verastem, Rootpath, Evaxion, Dragonfly, Jazz Pharmaceuticals. DFM receives consulting fees from Merck, Pfizer, Eisai, Cullinan and Arcus, receives clinical trial support from Merck, BMS and Genentech. AWS reports receiving Grants/Research Support (to the Institution) from Merck and Regeneron, consulting fees from Merck and Regeneron; royalties from UpToDate.

Figures

Figure 1
Figure 1. (A) Dosing schema for high dose IL-2 therapy and adjunctive HD IL-2 when given with TIL infusion. (B) Comparison of common toxicities between HD IL-2 dosing and IL-2 with TIL administration (adapted from Atkins et al and Chesney et al18). HD IL-2, high-dose bolus IL-2.
See this image and copyright information in PMC

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