The Combination of Oncolytic Virus and Antibody Blockade of TGF-β Enhances the Efficacy of αvβ6-Targeting CAR T Cells Against Pancreatic Cancer in an Immunocompetent Model.

BACKGROUND/OBJECTIVES: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. METHODS: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. RESULTS: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. CONCLUSIONS: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer.