Abstract 1582: Cabozantinib changes the tumor microenvironment to increase the efficacy of immunotherapy in refractory metastatic pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Tumors evade immune surveillance by expressing PD-L1 that interacts with the T cell protein PD-1, subsequently inhibiting CD8+ cytotoxic T lymphocyte proliferation and effector function. A plausible reason for this observation may be that other, redundant, immune suppressive mechanisms are at play. Our research team has shown that elevated infiltration of polymorphonuclear (PMN) -MDSCs within the PDAC tumor microenvironment (TME) inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition (Holokai et al. , 2020). Objective: A Phase II clinical trial was developed to identify the potential therapeutic benefit of combinatorial anit-PD-L1/PD-1 and cabozantinib (cabo) treatment in therapy-resistant (refractory and metastatic) PDAC patients. Methods: NanoString CosMx™ spatial molecular transcriptomic imaging (CosMx™ SMI) was performed using FFPE sections collected from a liver or lung metastatic target lesions at visit 1 (pretreatment) and visit 2 (9 weeks on combinatorial treatment) from individual patients. FFPE sections were prepared from the same target lesion, and fields of view were chosen on the H correlating with an increase in CD8 perforin and granzyme B positive cells in response to cabo and checkpoint inhibition. MxIF, spectral flow cytometry and scRNAseq analyses of the matched in vitro PDO model showed tumor cell death that correlated with decreased MDSC viability, increased CTL proliferation and a shift in CAF phenotypes. Conclusion: These findings suggest that cabo induces a TME conducive to increased response to immunotherapy in PDAC patients with refractory metastatic disease. Citation Format: Jayati Chakrabarti, Pritha Adhikary, Jiang Wang, Davendra Sohal, Syed A. Ahmad, Junaid Arshad, Aaron J. Scott, Rachna T. Shroff, Yana Zavros. Cabozantinib changes the tumor microenvironment to increase the efficacy of immunotherapy in refractory metastatic pancreatic ductal adenocarcinoma 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 (6Suppl): Abstract nr 1582.