Abstract A114: CCK-B Receptor Blockade with Proglumide Enhances Antitumor Activity and Persistence of CD8+CD161+ CAR-T Cells in Pancreatic Ductal Adenocarcinoma
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".