Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies

Abstract

Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette–Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803.

A landscape of checkpoint blockade resistance in cancer: underlying mechanisms and current strategies to overcome resistance

“… 160 Due to the short lifespan of rIL-15 in vivo , N803, an IL-15 superagonist composed of IL-15 mutant (IL-15N72D) complexed to a dimeric sushi domain of IL15Rα (IL-15 RαSu) and fused to an IgG-Fc fragment, was developed. 161 , 164 The combination of N803 and ICI has been the focus of several preclinical and clinical studies. In syngeneic breast and colon murine tumor models, the combination of N803 and PD-L1 blockade promoted the activation, proliferation, and cytotoxicity of CD8 + T cells and NK cells, resulting in decreased tumor burden ( Figure 2d ).…”

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

“…Growing evidence confirmed the use of N803 in combinatorial therapies, including those involved in the inhibition of suppressive phenotype often detected in the TME, with the intent to potentiate the effect of immune checkpoint inhibitors also in patients initially refractory to this kind of therapy [9].…”