Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model

Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model

Science Advances

10.1126/sciadv.add1187

http://dx.doi.org/10.1126/sciadv.add1187

Wai Nam Liu, Wing Yan So, Sarah L. 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 Poh Sheng Yeong, N. Gopalakrishna Iyer, Darren Wan-Teck Lim, Qingfeng Chen

Multidisciplinary

23 November 2022

Liu, W. N., So, W. Y., Harden, S. L., Fong, S. Y., Wong, M. X. Y., Tan, W. W. S., Tan, S. Y., Ong, J. K. L., Rajarethinam, R., Liu, M., Cheng, J. Y., Suteja, L., Yeong, J. P. S., Iyer, N. G., Lim, D. W.-T., & Chen, Q. (2022). Successful targeting of PD-1/PD-L1 with chimeric antigen receptor-natural killer cells and nivolumab in a humanized mouse cancer model. Science Advances, 8(47). https://doi.org/10.1126/sciadv.add1187

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.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

This research / project is supported by the National Research Foundation - Singapore Fellowship
Grant Reference no. : NRF-NRFF2017-03

This research / project is supported by the A*STAR - Career Development Award
Grant Reference no. : 20701/C210112003

This research / project is supported by the National Research Foundation - NRF-ISF joint grant
Grant Reference no. : NRF2019-NRF-ISF003-3127

This research / project is supported by the A*STAR - Industry Alignment Fund-Industry Collaboration Projects (IAF-ICP) Grant
Grant Reference no. : ICP-2000120

This research / project is supported by the National Medical Research Council - Clinician Scientist Individual Research Grant
Grant Reference no. : CIRG19may-0051

This research / project is supported by the A*STAR - Industry Alignment Fund-Industry Pre-positioning Program (IAF-PP) Grant
Grant Reference no. : H18/01/a0/022

This research / project is supported by the National Medical Research Council - Open Fund - Large Collaborative Grant (OF-LCG)
Grant Reference no. : OFLCG19May-0038

https://oar.a-star.edu.sg/communities-collections/articles/18829

2375-2548

Institute of Molecular and Cell Biology