Abstract 6313: Enhancing CAR T cell-based immunotherapy outcomes in PDAC: Evaluating iC9.B7-H3 CAR T cells in adjuvant, neoadjuvant, and monotherapy settings

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive and lethal cancers worldwide. Despite negative margin resections and subsequent systemic therapy, PDAC often recurs. Additionally, most patients present with locally advanced and unresectable tumors at the time of diagnosis. Cancer-associated fibroblasts (CAFs) contribute to the highly desmoplastic tumor microenvironment (TME) and form a biophysical barrier, limiting immune cell infiltration. Moreover, CAF-secreted factors suppress the anti-tumor activity of T cells and shift cancer cells toward invasive proliferative and mesenchymal phenotypes. Therefore, targeting CAFs can enhance T-cell infiltration and improve the efficacy of T-cell based immunotherapeutic strategies. B7-H3 is an immune checkpoint molecule highly expressed on PDAC cells and CAFs. In this study, we investigate the use of Chimeric Antigen Receptor (CAR) T cells targeting B7-H3 to eliminate metastatic PDAC in a preclinical mouse model in three different settings: I. Adjuvant II. Neoadjuvant III. CAR T cell monotherapy. Our CART-B7-H3 construct includes an inducible caspase 9 (iC9) suicide gene, which allows for the controlled elimination of the CAR T cells in the event of overwhelming cytokine release syndrome. Methods: To validate the therapeutic potential of iC9.B7-H3 CAR T cells in vivo, NSG mice were orthotopically engrafted with 1x105 patient-derived PDAC6 cells and 9x105 hCAF1 cells at a ratio of 1:9, reflecting a clinically relevant model. In the adjuvant group, mice underwent surgical resection of the primary tumor (distal pancreatectomy and splenectomy) after 25 days. On days 30 and 60, they received systemic iC9.B7-H3 CAR T cell treatment (5x106). In the neoadjuvant group, mice were systemically treated with iC9.B7-H3 CAR T cells on day 19 and underwent surgical resection of the primary tumor on day 25, following another systemic CAR T cell dose on day 60. In the CAR T monotherapy group, mice received systemic iC9.B7-H3 CAR T cells on days 19 and 60. Results: In vivo, iC9.B7-H3 CAR T cells in the neoadjuvant group effectively eradicated both local and distant PDAC metastases for the length of the experiment (180 days) and significantly increased the survival (P <0.0001), indicating long-term efficacy in the treatment of PDAC metastases with no adverse side effects. In the adjuvant and CAR T monotherapy groups, iC9.B7-H3 CAR T cells effectively control tumor growth, eliminate metastases, and significantly increase survival (P=0.0018 and P=0.0007, respectively). Conclusion: These data suggest that the neoadjuvant application of iC9.B7-H3 CAR T cells may demonstrate persistent efficacy in eradicating both local and distant PDAC metastases. iC9.B7-H3 CAR T cells adjuvantly and as monotherapy achieved significant tumor control. Citation Format: Shahrzad Arya, Seyed Amir Sanatkar, Marco Ventin, Giulia Cattaneo, Cristina Martin, Gabriella Lionetto, Jingyu Jia, Feng Chen, David T. Ting, Xinhui Wang, Sandra Ryeom, Cristina R. Ferrone, Soldano Ferrone. Enhancing CAR T cell-based immunotherapy outcomes in PDAC: Evaluating iC9.B7-H3 CAR T cells in adjuvant, neoadjuvant, and monotherapy settings [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 6313.