Solid tumor CAR T cells engineered with fusion proteins targeting PDL1 for localized IL-12 delivery
Year: 2025
Type: preprint
Abstract: CAR T cell efficacy in solid tumors is limited due in part to the immunosuppressive TME. To improve anti-tumor responses, we hypothesized that enabling CAR T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier (e.g., TGFβtrap, IL15, or IL12) combined with an immune checkpoint inhibitor (e.g., αPDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality. To that end, we engineered CAR T cells to secrete TGFβtrap, IL15, or IL12 molecules fused to αPDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with αPDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with αPDL1 fused with TGFβtrap or IL15. Further, αPDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFNγ production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities. We believe our αPDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.
Institutions: University of Southern California, City Of Hope National Medical Center, City of Hope, Georgia Institute of Technology, The Wallace H. Coulter Department of Biomedical Engineering, University of Pennsylvania, Imperial College London, University of California, Los Angeles, University of South Florida
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4409288054