Rafiq et al. modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFvs) and demonstrated improved survival of mice with syngeneic and xenogeneic hematologic and solid tumors compared to standard CAR-T cells. Compared with the combination of standard CAR-T cells and systemic anti-PD-1, the modified CAR-T cells were equally or more effective. The treatment led to functionally relevant bystander binding of scFvs to tumor-specific T cells, and to the formation of memory response. As the secreted PD-1-blocking scFvs remain local to the tumor, systemic toxicities may be reduced.
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1(+) hematologic and solid tumors. The efficacy was similar to or better than that achieved by combination therapy with CAR-T cells and a checkpoint inhibitor. This approach may improve safety, as the secreted scFvs remained localized to the tumor, protecting CAR-T cells from PD-1 inhibition, which could potentially avoid toxicities associated with systemic checkpoint inhibition.
Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, New Yor
Author Info: (1) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (2) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (3) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (4) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (5) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (6) Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA. (7) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA. (8) Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (9) Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (10) Eureka Therapeutics Inc., Emeryville, California, USA. (11) Eureka Therapeutics Inc., Emeryville, California, USA. (12) Eureka Therapeutics Inc., Emeryville, California, USA. (13) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA. (14) Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (16) Eureka Therapeutics Inc., Emeryville, California, USA. (17) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Cellular Therapeutics Center, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
