2022 update on the scientific premise and clinical trials for IL-15 agonists as cancer immunotherapy

Abstract

Diverse cytokines and their receptors on immune cells constitute a highly complex network in the immune system. Some therapeutic cytokines and their derivatives have been approved for cancer treatment. IL‐15 is an immune‐regulating cytokine with multiple functions, among which the function of activating the immunity of cancer patients has great potential in cancer immunotherapy. In this review, we introduce the functions of IL‐15 and discuss its role in regulating the immune system in different immune cells. Meanwhile, we will address the applications of IL‐15 agonists in cancer immunotherapy and provide prospects for the next generation of therapeutic designs. Although many challenges remain, IL‐15 agonists offer a new therapeutic option in the future direction of cancer immunotherapy.

Oncolytic Adenoviruses Armed with Co-Stimulatory Molecules for Cancer Treatment

“…Interleukin 15 is a small peptide of around 14–15 kDa, classified to the 4-α-helix family, similarly to IL-2 [ 102 , 103 ]. IL-15 is responsible for promoting the proliferation and stimulation of the activity of many immunologic cells: NK, NKT, CD8 + , and DC.…”

“…IL-15 does not cause severe capillary leak syndrome, making it safer in oncolytic therapies than IL-2 [ 92 , 105 ]. However, the use of IL-15 is limited due to its short lifetime and biostability [ 103 ]. The latest studies have focused on IL-15 agonist.…”

“…It is a complex of wild-type IL-15 and soluble IL-15R-α. Studies have shown that IL-15 agonist stimulates the immune system more strongly than wild-type cytokine [ 103 ]. What is more, agonists significantly increased the half-life of IL-15.…”

“…In many studies, IL-15 agonists improved cancer degradation compared to wild-type IL-15 [ 104 ]. Viral delivery of IL-15 and IL-15 agonists was examined as a potentially more effective and less toxic approach [ 103 , 104 ]. Kowalsky et al [ 104 ] reported that delivering IL-15 agonist by oncolytic vaccinia virus improved cancer reduction.…”

Targeted LNPs deliver mRNA encoding IL-15 superagonists to balance efficacy and toxicity in cancer therapy

“…The biological effects of IL-15 are mediated through interaction with a receptor complex comprising three distinct chains: CD122 (IL-2/IL-15Rβ), CD132 (IL-2/IL-15Rγc), and the high-affinity-specific chain IL-15Rα (3). IL-15 currently has garnered considerable attention as a promising immunotherapeutic candidate for cancer treatment (4,5), exemplified by the advancement of the IL-15 analogue and agonist complex agent nogapendekin alfa (N-803) (6)(7)(8)(9), as well as the ongoing clinical trials of similar agents (10)(11)(12). However, potential toxicity remains due to the mechanism by which IL-15 superagonists activate T/NK cells (13)(14)(15).…”