The potential and promise of IL-15 in immuno-oncogenic therapies

Abstract

This review provides an in-depth description of the preclinical and clinical studies demonstrating the effectiveness and limitations of IL-15 and IL-15 analogs given as an exogenous immuno-oncology agent. IL-15 is a cytokine that primarily stimulates the proliferation and cytotoxic functions of CD8 T cells and NK cells leading to enhanced anti-tumor responses. While initially showing promise as a cancer therapeutic, the efficacy of IL-15 was limited by its short in vivo half-life. More recently, various approaches have been developed to improve the in vivo half-life and efficacy of IL-15, largely by generating IL-15/IL-15Rα conjugates. These new IL-15 based agents renew the prospect of IL-15 as a cancer immunotherapeutic agent. While having some efficacy in inducing tumor regression as a monotherapy, IL-15 agents also show great potential in being used in combination with other immuno-oncological therapies. Indeed, IL-15 used in combination therapy yields even better anti-tumor responses and prolongs survival than IL-15 treatment alone in numerous murine cancer models. The promising results from these preclinical studies have led to the implementation of several clinical trials to test the safety and efficacy of IL-15-based agents as a stand-alone treatment or in conjunction with other therapies to treat both advanced solid tumors and hematological malignancies.

Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

“…This difference was also observed for the corresponding ΔLNGFR surrogate and for IL-12P70, found to be secreted over a longer time by TRAC CAR _ΔPD1 IL12m than by TRAC CAR _CD25 IL12m . Similar results were obtained when IL-15/IL-15rα was substituted for IL-12P70, demonstrating the robustness and transposability of our approach to express proteins of therapeutic interest 44,45 in a tumor cell-dependent manner ( Supplementary Fig. 4).…”

Interleukin-15-Stimulated Natural Killer Cells Clear HIV-1-Infected Cells following Latency Reversal Ex Vivo

“…Thus, NK cell function might be improved by using other priming strategies, such as IFN-␣ stimulation (29,30) or therapeutic vaccination (31). In addition, clinical experience gained in oncology may be leveraged to design HIV-specific approaches, given the more advanced stages of NK cell-based therapies that have been developed for cancer (32)(33)(34)(35)(36).…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…In consequence, high doses are required for therapeutic effect that leads to toxicity. To address this issue, several different genetic modifications of IL-15 were developed to prolong its half-life, which resulted in an enhanced anti-tumour response in animal models [199]. Currently, clinical trials are ongoing to assess anti-cancer potency of an IL-15 variant called ALT-803.…”