Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model
Wai Nam Liu, Wing Yan So, Sarah Harden, Shin Yie Fong, Melissa Xin Yu Wong, Wilson Wei Sheng Tan, Sue Yee Tan, Jessica Kai Lin Ong, Ravisankar Rajarethinam, Min Liu, Jia Ying Cheng, Lisda Suteja, Joe Yeong, N. Gopalakrishna Iyer, Wan‐Teck Lim, Qingfeng Chen
Abstract
In recent decades, chimeric antigen receptor (CAR)–engineered immune effector cells have demonstrated promising antileukemic activity. Nevertheless, their efficacy remains unsatisfactory on solid cancers, plausibly due to the influence of tumor microenvironments (TME). In a novel mouse cancer model with a humanized immune system, tumor-infiltrating immunosuppressive leukocytes and exhausted programmed death protein-1 (PD-1) high T cells were found, which better mimic patient TME, allowing the screening and assessment of immune therapeutics. Particularly, membrane-bound programmed death ligand 1 (PD-L1) level was elevated on a tumor cell surface, which serves as an attractive target for natural killer (NK) cell–mediated therapy. Hematopoietic stem cell–derived CAR-NK (CAR pNK) cells targeting the PD-L1 showed enhanced in vitro and in vivo anti-solid tumor function. The CAR pNK cells and nivolumab resulted in a synergistic anti-solid tumor response. Together, our study highlights a robust platform to develop and evaluate the antitumor efficacy and safety of previously unexplored therapeutic regimens.