Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting

Eric Hee Jun Lee, John P. Murad, Lea Christian, Jackson Gibson, Yukiko Yamaguchi, Cody Cullen, Diana Gumber, Anthony K. Park, Cari Young, Isabel Monroy, Jason Yang, Lawrence A. Stern, Lauren N. Adkins, Gaurav Dhapola, Brenna Gittins, Wen-Chung Chang, Catalina Martinez, Yanghee Woo, Mihaela Cristea, Lorna Rodriguez-Rodriguez, Jun Ishihara, John K. Lee, Stephen J. Forman, Leo D. Wang and Saul J. Priceman ()
Additional contact information
Eric Hee Jun Lee: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
John P. Murad: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Lea Christian: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Jackson Gibson: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Yukiko Yamaguchi: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Cody Cullen: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Diana Gumber: Beckman Research Institute of City of Hope
Anthony K. Park: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Cari Young: Beckman Research Institute of City of Hope
Isabel Monroy: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Jason Yang: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Lawrence A. Stern: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Lauren N. Adkins: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Gaurav Dhapola: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Brenna Gittins: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Wen-Chung Chang: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Catalina Martinez: Department of Clinical and Translational Project Development, City of Hope
Yanghee Woo: Department of Surgery, City of Hope
Mihaela Cristea: Department of Medical Oncology and Therapeutics Research, City of Hope
Lorna Rodriguez-Rodriguez: Department of Surgery, City of Hope
Jun Ishihara: Imperial College London
John K. Lee: Human Biology Division, Fred Hutchinson Cancer Center
Stephen J. Forman: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope
Leo D. Wang: Beckman Research Institute of City of Hope
Saul J. Priceman: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Chimeric antigen receptor (CAR) T cell therapeutic responses are hampered by limited T cell trafficking, persistence, and durable anti-tumor activity in solid tumors. However, these challenges can be largely overcome by relatively unconstrained synthetic engineering strategies. Here, we describe CAR T cells targeting tumor-associated glycoprotein-72 (TAG72), utilizing the CD28 transmembrane domain upstream of the 4-1BB co-stimulatory domain as a driver of potent anti-tumor activity and IFNγ secretion. CAR T cell-mediated IFNγ production facilitated by IL-12 signaling is required for tumor cell killing, which is recapitulated by engineering an optimized membrane-bound IL-12 (mbIL12) molecule in CAR T cells. These T cells show improved antigen-dependent T cell proliferation and recursive tumor cell killing in vitro, with robust in vivo efficacy in human ovarian cancer xenograft models. Locoregional administration of mbIL12-engineered CAR T cells promotes durable anti-tumor responses against both regional and systemic disease in mice. Safety and efficacy of mbIL12-engineered CAR T cells is demonstrated using an immunocompetent mouse model, with beneficial effects on the immunosuppressive tumor microenvironment. Collectively, our study features a clinically-applicable strategy to improve the efficacy of locoregionally-delivered CAR T cells engineered with antigen-dependent immune-modulating cytokines in targeting regional and systemic disease.

Date: 2023
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DOI: 10.1038/s41467-023-40115-1

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