Abstract A114: CCK-B Receptor Blockade with Proglumide Enhances Antitumor Activity and Persistence of CD8+CD161+ CAR-T Cells in Pancreatic Ductal Adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, with a 5-year survival rate of only 13%. Resistance to immunotherapy is largely attributed to PDAC’s dense, fibrotic, and highly immunosuppressive tumor microenvironment (TME), which impedes immune cell infiltration and promotes T cell dysfunction. A key contributor to this fibrotic and immunosuppressive landscape is the activation of pancreatic stellate cells and cancer-associated fibroblasts (CAFs) via cholecystokinin-B receptors (CCK-BRs). Proglumide, a selective CCK-BR antagonist, has previously been shown to reduce tumor-associated fibrosis, shift macrophages toward a pro-inflammatory phenotype, enhance CD8+ T cell infiltration, and inhibit metastatic spread. These effects suggest that proglumide may serve as an effective TME-modulating agent to potentiate adoptive cell therapies in PDAC. Concurrently, we identified a subset of human CD8 + T cells expressing CD161 (murine homolog is NK1.1), associated with enhanced cytotoxicity, granzyme B expression, tissue homing, and memory-like phenotype with reduced exhaustion levels. CD8+CD161+ T cells engineered with a HER2-targeted chimeric antigen receptor (CAR) demonstrated significantly improved tumor-killing capacity compared to conventional CAR-T cells in HER2+ PDAC models. In this study, we evaluated the therapeutic potential of combining proglumide with CD8 + CD161 + HER2-directed CAR-T cells in immunodeficient SCID mice bearing either subcutaneous or intraperitoneal luciferase-labeled PANC-1 tumors. Across three independent experiments, combination therapy resulted in significantly reduced tumor burden and improved overall survival compared to monotherapy with either proglumide or CAR-T cells alone (p=0.0120 and p=0.0005, respectively). Bioluminescent imaging confirmed enhanced tumor regression in the combination group, and TME analysis by flow cytometry demonstrated increased CAR-T cell infiltration into the tumors in mice treated with combination therapy. To further evaluate the durability of the response, we performed tumor rechallenge experiments using luciferase-negative PANC-1 cells. Mice that had previously received combination therapy exhibited a trend toward lower tumor burden and delayed tumor growth compared to those that had received CAR-T cells alone. These results suggest that proglumide not only improves CAR-T cell access and function but may also support memory, contributing to long-term tumor control. In conclusion, our findings support a novel immunotherapeutic strategy in PDAC involving pharmacologic remodeling of the TME using CCK-BR blockade in combination with enhanced CAR-T cell products. This approach holds promise for overcoming the immune exclusion and fibrotic barriers characteristic of PDAC, and it may significantly enhance both the efficacy and persistence of adoptive T cell therapies in this challenging disease setting. Further studies are underway to evaluate this strategy in orthotopic and spontaneous PDAC models, as well as to explore translational potential in clinical trials. Citation Format: Nalini Bisht, Keenan J. Ernste, Sharon Amanya. Bright, Harrison Berger, Sruthi Panja, Sujith K. Joseph, Willam K. Decker, Jill P. Smith, Vanaja Konduri. CCK-B Receptor Blockade with Proglumide Enhances Antitumor Activity and Persistence of CD8+CD161+ CAR-T Cells in Pancreatic Ductal Adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A114.