Abstract 1435: Utilization of CLDN18.2 syngeneic mouse models to study chimeric antigen receptor T cells in immunocompetent mice

Abstract

Abstract CLDN18.2 expression has been observed in pancreatic, gastric and esophageal cancers, whereas normal tissue expression of CLDN18.2 is mostly restricted to differentiated gastric mucosal epithelial cells. This expression profile renders CLDN18.2 an ideal tumor associated antigen (TAA) for CAR-T targeting and an armored targeted CAR-T, AZD6422, is in clinical development. While CAR-T are beginning to show clinical promise in solid tumors, a consistent challenge is to overcome the immunosuppressive tumor microenvironment (TME) where immune and stromal cells secrete high levels of TGFb. Since the majority of pre-clinical CAR-T efficacy data is generated utilizing immunocompromised mouse models, which lack a proper TME, the team utilized syngeneic xenograft models to circumvent this challenge. ​ In vitro studies showed that CLDN18.2 targeted murine CAR-T cells generated by retroviral transduction induced efficient cytolysis of target positive mouse tumor cells accompanied by cytokine release. To model the clinical scenario, tumor-bearing mice were lymphodepleted with total body irradiation (TBI) to enhance CAR-T engraftment. The dosage of TBI used in these studies was predetermined to have caused leukopenia and minimal impact on tumor growth. We observed substantial tumor control and extended tumor efficacy in mice treated with mCAR-T cells compared to those infused with untransduced T cells or in non-target bearing control tumors in the absence of gross toxicities. ​ This syngeneic mouse model platform will additionally allow us to investigate how mCAR-T cells perform within a fully competent TME in combination with other therapeutic agents targeting cancer cells via altered mechanism of action. ​ Citation Format: Shannon Breen, Rosa Carrasco, Kelly McGlinchey, Brianna Janocha, Peter Zanvit, Lorenzo Ortiz, Benjamin Clark, Aleksandra Toloczko, Mark Cobbold, Gordon Moody, Emily Bosco, Allison Barrett. Utilization of CLDN18.2 syngeneic mouse models to study chimeric antigen receptor T cells in immunocompetent mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1435.