To improve CAR T cell efficacy in solid tumors, Murad et al. armored CAR T cells to secrete bifunctional fusion proteins consisting of TGFβtrap, IL-15, or IL-12 tethered to anti-PD-L1, enabling local and targeted antitumor effects with reduced systemic toxicity. In immunologically “cold” syngeneic prostate and ovarian models, anti-PD-L1 fused to IL-12 outperformed CAR T cells alone and the other combinations in efficacy and safety, enhancing T cell trafficking into the tumor, TME modulation, and localized IFNγ production, with less systemic cytokine-associated toxicity. An active human version of anti-PD-L1–IL-12 fusion was also generated.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor (CAR)-T cell efficacy in solid tumours is limited due in part to the immunosuppressive tumour microenvironment (TME). To improve antitumour responses, we hypothesized that enabling CAR-T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier such as TGFβtrap, IL-15 or IL-12, combined with an immune checkpoint inhibitor such as αPD-L1, would provide tumour-localized immunomodulation to improve CAR-T cell functionality. Here we engineer CAR-T cells to secrete TGFβtrap, IL-15 or IL-12 molecules fused to αPD-L1 scFv and assess in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR-T cells engineered with αPD-L1-IL-12 are superior in safety and efficacy compared with CAR-T cells alone and those engineered with αPD-L1 fused with TGFβtrap or IL-15. Further, αPD-L1-IL-12 engineered CAR-T cells improve T cell trafficking and tumour infiltration, and localize IFNγ production, TME modulation and antitumour responses, with reduced systemic inflammation-associated toxicities. We believe our αPD-L1-IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types.
Author Info: (1) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine o
Author Info: (1) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (2) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (3) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (4) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (5) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (6) Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech College of Engineering and Emory School of Medicine, Atlanta, GA, USA. (7) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (8) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (9) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (10) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (11) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (12) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (13) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (14) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. (15) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (16) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. (17) Department of Bioengineering, Imperial College London, London, UK. (18) Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA, USA. (19) Department of Chemical, Biological, and Materials Engineering, University of South Florida, Tampa, FL, USA. (20) Keck School of Medicine (KSOM)/Norris Center for Cancer Cellular Immunotherapy Research (CCCIR), Division of Medical Oncology, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA. priceman@usc.edu. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA. priceman@usc.edu.
