Interleukin 15 in Cell-Based Cancer Immunotherapy

Abstract

Cell-based cancer immunotherapy, such as chimeric antigen receptor (CAR) engineered T and natural killer (NK) cell therapies, has become a revolutionary new pillar in cancer treatment. Interleukin 15 (IL-15), a potent immunostimulatory cytokine that potentiates T and NK cell immune responses, has demonstrated the reliability and potency to potentially improve the therapeutic efficacy of current cell therapy. Structurally similar to interleukin 2 (IL-2), IL-15 supports the persistence of CD8⁺ memory T cells while inhibiting IL-2-induced T cell death that better maintains long-term anti-tumor immunity. In this review, we describe the biology of IL-15, studies on administrating IL-15 and/or its derivatives as immunotherapeutic agents, and IL-15-armored immune cells in adoptive cell therapy. We also discuss the advantages and challenges of incorporating IL-15 in cell-based immunotherapy and provide directions for future investigation.

Keywords: NK cell; T cell; adoptive cell transfer; cancer; chimeric antigen receptor; engineering; immunotherapy; interleukin 15.

Figure 1

IL-15 and its therapeutic applications. (a) The structure and downstream signaling of IL-15 and its receptor complex. IL-15 is trans-presented on antigen-presenting cells by IL-15Rα, which interacts with the β chain (IL-2/15Rβ) and common γ chain (γc) complex on effector cells. Upon activation, the β and γc receptor triggers the intracellular signaling of the Janus kinase pathway, which stimulates the signal transducer and activator of transcription (STAT) proteins downstream. The phosphorylated STATs relocate to the nucleus, modifying gene expression. (b) IL-15 derivatives and their structure. From left, Escherichia coli-derived IL-15 monomer (sch rhIL-15), Receptor-Linker-IL-15 fusion protein consisting of IL-15 linked to the sushi domain of IL-15Rα (RLI), IL-15 heterodimer with soluble IL-15Rα (hetIL-15/NIZ985), another form of hetIL-15 where C-terminus of IL-15Rα is linked to the Fc region of human IgG1 (hetIL-15Fc), N72D mutant and human Il-15Rα sushi domain-Fc fusion protein (N-803/ALT-803) and polyethylene glycol-conjugate of rhIL-15 (NKTR-255). (c) IL-15 armored immune cells. The starting population of T, NK, γδT, iNKT cells collected from healthy donors are engineered and differentiated into therapeutic cells armored with soluble IL-15 (sIL-15) and CAR, or membrane-bound IL-15 (mbIL-15) and CAR. Co-expressing IL-15 or mbIL-15 with CAR enhances immune cells proliferation and expansion, increases anti-tumor activity and effectiveness, improves viability and cellular fitness, and increases stem memory.

Figure 2

Mechanism of IL-15 Armored CAR T Cells. IL-15-armored CAR T cells mechanism of action. The engineered cells with the CAR and IL-15 transgene secrete soluble IL-15 (sIL-15), which either gets recognized directly by the endogenous IL-15 receptor or captured by neighboring Antigen Presenting Cells (APCs). After receiving the IL-15 signal, downstream signaling pathways include the PI3K/AKT signaling pathway, Ras/Raf MAPK signaling pathway, and JAK/STAT signaling pathway. These three pathways together control various gene expressions: upregulating Bcl-2, Bcl-Xl, Mcl-1 (anti-apoptotic), downregulating Bim, Puma (pro-apoptotic), upregulating c-Myc, c-Fos, c-Jun (proliferation), NF-κB (pro-inflammatory) and inducing the release of TNF-α, IFN-γ (cytotoxicity). On the left is a diagram representation of tumor recognition through CAR. CAR constructs include CD19-CAR, IL13Rα-CAR, Fn14-CAR, CD123-CAR, GPC3-CAR, GD2-CAR, and CD5-CAR et al.