Rethinking Oncologic Treatment Strategies with Interleukin-2

Abstract

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 narrow therapeutic window of IL-2 by leveraging downstream activation of the IL-2 receptor to selectively expand anti-tumor CD8-positive T cells and natural killer cells. These modified IL-2 cytokines improve single-agent activity in solid tumor malignancies beyond the established United States Food and Drug Administration (FDA) indications of metastatic melanoma and renal cell carcinoma, and may also be safer in rational combinations with established treatment modalities, including anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches.

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing

“…Noteworthy partial responses were also noted in patients with platinum-resistant ovarian cancer, alongside instances of stable disease across various other cancers. These initial findings suggest that nemvaleukin alfa may offer advantages over other IL-2 variants [89,90].…”

“…Unlike conventional recombinant IL-2, nemvaleukin alfa retains stability in circulation and does not necessitate metabolic activation. By specifically targeting receptor complexes, nemvaleukin alfa endeavors to alleviate the severe immune-related toxicities associated with high-dose IL-2 therapy [89]. The ARTISTRY-1 trial (NCT02799095) investigated the efficacy of nemvaleukin alfa in treating advanced solid tumors through various approaches, including dose escalation, monotherapy expansion, and combination therapy with pembrolizumab.…”

Emerging Treatments Targeting the Tumor Microenvironment for Advanced Chondrosarcoma

“…Their impressive ability to elicit antitumor immune responses in solid tumors has encouraged investigations into their potential beneficial effects for ChS patients. Furthermore, aldesleukin, a recombinant form of human interleukin-2 that stimulates proliferation and maturation of the CD8-positive T- and natural killer-cells, has been shown to elicit promising outcomes in advanced solid tumors [ 113 ].…”

Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies

“…This is a consequence of the high toxicity observed after administration of IL-2; moreover, IL-2 is also responsible for T-reg activation, a population often present in the TME, as the main responsible for the failure of immunotherapy. For this reason, the review by Ko et al [8] proposed new strategies to overcome these limitations. They reported the employment of new synthetic IL-2-fusion protein variants to increase the anti-cancer properties and simultaneously reduce the ability to stimulate immune T-reg cells in the TME, responsible for blocking cytotoxic T-cell activities.…”