经靶向 PDL1 融合蛋白改造的实体瘤 CAR-T 细胞用于局部 IL-12 递送

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. , TGF trap, IL15, or IL12) combined with an immune checkpoint inhibitor (e. g. , PDL1) will provide tumor localized immunomodulation to improve CAR T cell functionality.

To that end, we engineered CAR T cells to secrete TGF trap, IL15, or IL12 molecules fused to PDL1 scFv, and assessed in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR T cells engineered with PDL1-IL12 were superior in safety and efficacy compared to CAR T cells alone and to those engineered with PDL1 fused with TGF trap or IL15.

Further, PDL1-IL12 engineered CAR T cells improved T cell trafficking and tumor infiltration, localized IFN production, TME modulation, and anti-tumor responses, with reduced systemic inflammation-associated toxicities.

We believe our PDL1-IL12 engineering strategy presents an opportunity to improve CAR T cell clinical efficacy and safety across multiple solid tumor types.