To efficiently target IL15 to intratumoral PD-1+ TILs, Xu et al. generated a fusion protein of a potency-reduced IL15 mutein and a mouse- or human-specific PD-1-specific antibody (anti-PD1–IL15m). At low non-toxic dose, anti-mPD1–IL15m preferentially targeted CD8+ TILs, showed superior antitumor efficacy in a CD8+ T cell-dependent manner, and led to expansion of an exhausted CD8+ TIL cluster with high proliferative capacity and effector-like signatures in B16 and MC38 syngeneic tumor models. Anti-hPD1–IL15m enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human cancers in vitro, but did not affect Tregs.
Contributed by Shishir Pant
ABSTRACT: The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD-1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD-1-mediated, avidity-driven IL2/15 receptor stimulation to PD-1+ tumor-infiltrating lymphocytes (TILs) while minimally affecting circulating peripheral natural killer (NK) cells and T cells. Treatment of tumor-bearing mice with a mouse cross-reactive fusion, anti-mPD1-IL15m demonstrated potent antitumor efficacy without exacerbating body weight loss in B16 and MC38 syngeneic tumor models. Moreover, anti-mPD1-IL15m was more efficacious than an IL15 superagonist, an anti-mPD-1, or the combination thereof in the B16 melanoma model. Mechanistically, anti-PD1-IL15m preferentially targeted CD8+ TILs and scRNA-seq analyses revealed that anti-mPD1-IL15m treatment induced the expansion of an exhausted CD8+ TILs cluster with high proliferative capacity and effector-like signatures. Antitumor efficacy of anti-mPD1-IL15m was dependent on CD8+ T cells, as depletion of CD8+ cells resulted in the loss of antitumor activity, whereas depletion of NK cells had little impact on efficacy. The impact of anti-hPD1-IL15m on primary human TILs from cancer patients was also evaluated. Anti-hPD1-IL15m robustly enhanced the proliferation, activation, and cytotoxicity of CD8+ and CD4+ TILs from human primary cancers in vitro, whereas tumor-derived regulatory T cells were largely unaffected. Taken together, we showed that anti-PD1-IL15m exhibits a high translational promise with improved efficacy and safety of IL15 for cancer immunotherapy via targeting PD-1+ TILs.
Author Info: (1) CID, Pfizer (United States). (2) Department of Hepatology and Gastroenterology, Erasmus MC. (3) Protein Engineering, Rinat, Inc. (4) Pfizer (United States). (5) Oncology Resear
Author Info: (1) CID, Pfizer (United States). (2) Department of Hepatology and Gastroenterology, Erasmus MC. (3) Protein Engineering, Rinat, Inc. (4) Pfizer (United States). (5) Oncology Research Unit, Pfizer (United States). (6) Pfizer (United States). (7) Biology, Pfizer (United States). (8) Pfizer (United States). (9) Gastroenterology and Hepatology, Erasmus MC. (10) Gastroenterology and Hepatology, Erasmus MC. (11) Cancer Immunology Discovery, Pfizer (United States). (12) Pfizer (United States). (13) Cancer Immunology Discovery, Pfizer (United States). (14) Pfizer (United States). (15) Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc. (16) Gastroenterology and Hepatology, Erasmus MC. (17) Gastroenterology and Hepatology, Erasmus MC. (18) Pathology, Erasmus MC. (19) Pfizer (United States). (20) Surgery, Erasmus MC. (21) BMD, Pfizer Inc. (22) Surical Oncology, Erasmus MC Cancer Institute. (23) Amsterdam UMC. (24) Pathology, Amsterdam UMC. (25) Pathology, Erasmus MC. (26) Colorectal Surgery, IJsselland Ziekenhuis. (27) Pfizer (United States). (28) Cancer Immunology Discovery Unit, Pfizer Inc. (29) Pfizer (United States). (30) Pfizer (United States). (31) Oncology Research Unit, Pfizer (United States). (32) Pfizer Inc. (33) Pfizer (United States). (34) Pfizer (United States). (35) Pfizer (United States). (36) Computational Biology/Oncology Research Unit, Pfizer Global R & D. (37) BioMedicine Design, Pfizer (United States). (38) Drug safety R&D, Pfizer (United States). (39) Halozyme Therapeutics, Inc. (40) PDM, Pfizer Inc. (41) Pfizer (United States). (42) Gastroenterology and Hepatology, Erasmus MC. (43) Gastroenterology and Hepatology, Erasmus MC. (44) Pfizer (United States). (45) Pfizer Inc javier.chaparro-riggers@pfizer.com.
