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.

Keywords: Anktiva®; IL-15; N803; cancer immunotherapy; cytokine.

Figure 1

Pleiotropic effects of IL-15. The cytokine IL-15 is produced by multiple cell types, such as activated dendritic cells, monocytes/macrophages, epithelial cells, and bone marrow (BM) stromal cells. IL-15 is critical for natural killer (NK) cell lineage development, survival, and proliferation. This cytokine holds important modulatory effects in the expansion and survival of CD8⁺ T cells, including memory formation, and lymphocyte cytotoxic function. In addition, IL-15 has pleiotropic effects on peripheral innate and adaptive immunity. Schematic adapted from ([23]; Copyright © 2001 American Society of Hematology) and created with BioRender.com.

Figure 2

Immune effects of N803. (A) N803 comprises mutated (N72D) human IL-15 bound to the IL15Rα fused with a human IgG1 Fc. (B) N803 binds to circulating immune cells through the IL-15 receptor. (C) The binding of N803 to lymphocytes leads to the activation and expansion of natural killer (NK) cells and CD8⁺ T-cell populations, resulting in the expansion of high effector CD56^dim and CD56^bright NK cells and central memory T cells (T_CM). (D) The upregulation of CXCR3 on the surface of splenic CD8⁺ T cells increases the potential for homing into the tumor microenvironment (TME). Activated NK cells also migrate to the tumor. (E) Activated tumor-infiltrating CD8⁺ T lymphocytes (TILs) recognize cancer cells through recognition of the tumor-associated antigen epitopes presented by the MHC class I complex. Activated CD8⁺ T cells and NK cells display enhanced cytotoxicity leading to cancer cell death. CD8⁺ T cells release Th1 cytokines such as IFNγ and TNF⍺, promoting an inflamed TME and upregulating PD-L1 on granulocytic and monocytic myeloid-derived suppressor cells (MDSCs). N803 renders NK TILs resistant to the effects of TGF-β and capable of enhanced antibody-dependent cellular cytotoxicity (ADCC). Figure created with BioRender.com.

Figure 3

N803 favors the expansion of natural killer (NK) cells and CD8⁺ T cells in healthy volunteers. (A) Study design [59]. N803 was administered subcutaneously at 10 μg/kg on day 1 of study period 1 and 20 μg/kg on day 1 of study period 2. Subjects in group A and group B were administered 1.0 and 2.0 mg/mL N803, respectively. Blood samples for pharmacokinetic analysis were collected (red arrowheads) over nine consecutive days after each N803 administration. On day 1 in both study periods, blood samples were collected before N803 administration, and at 1 and 4 h after administration. (B,C) The number of CD8⁺ T cells, CD4⁺ T cells, and NK cells per μL of blood and respective Ki67 expression in (B) study period 1 and (C) study period 2. Graphs show the mean values (lines) and S.E.M. (shading). All panels were adapted from [59]; Copyright 2022. The American Association of Immunologists, Inc.

Figure 4

Immune correlates (A,B) and clinical effects (C,D) in cancer patients treated with N803 plus nivolumab. Fold change versus baseline in (A) peripheral natural killer (NK) cell numbers and (B) Ki67 expression (MFI) in NK and T–cell subsets on day 4. Each symbol represents one patient, with colors denoting the best response as depicted in the graph inset. (C) The best clinical response attained in patients treated with combination therapy using nivolumab at 3 mg/kg followed by a 240 mg flat dose. Upward arrow denotes one patient with 180% increase in tumor lesion size per RECIST criteria. Right arrows denote patients with ongoing study treatment. (D) Objective responses and disease control rates. Figure adapted from ([62]; Copyright 2018, with permission from Elsevier). * Progression due to a new lesion. † Target lesion decreased 27% but met RECIST 1.1 criteria for partial response. ** p < 0.001. *** p < 0.0001.

Figure 5

Clinical responses to intravesical N803 plus Bacillus Calmette–Guerin (BCG) therapy in non-muscle-invasive bladder cancer (NMIBC) patients treated in Phase Ib (A) and Phase II/III (B,C) clinical studies. (A) N803 dose, patient characteristics, and therapy response in nine patients treated in the Phase Ib study [66,67]. CR: complete response; NR: no recurrence; No CR: no complete response; IC: inconclusive; * only patient to experience disease recurrence. Noted at 38 months (carcinoma in situ (CIS)) and treated off study with N803 plus BCG, followed by maintenance BCG. After additional 28 months of follow-up, the patient was disease-free with intact bladder. (B,C) Duration of complete response in CIS (B) and papillary (pap) (C) disease patients treated with N803 and BCG in the Phase II/III clinical study [68]. Panel A adapted from ([67]; © 2021 Rosser et al. Published with license by Taylor & Francis Group, LLC). Panels (B,C) adapted from [68]; see also Chamie et. al., NEJM Evid 2023, DOI: 10.1056/EVIDoa2200167.