P02.11 Impact of systemic polychemotherapy in patients with pancreatic ductal adenocarcinoma on CAR T cell production and function

Background Pancreatic ductal adenocarcinoma (PDAC) remains a major clinical challenge, characterized by late diagnosis, limited therapeutic options and poor prognosis. With only a small percentage of patients qualifying for surgical removal, systemic treatment with chemotherapy continues to represent the backbone of PDAC therapy. In recent years, chimeric antigen receptor (CAR) T cell therapy has reshaped the treatment landscape of cancer and fueled high expectations as a potential therapeutic option in difficult-to-control diseases such as PDAC. Its efficacy however remains variable and predominantly restricted to hematological malignancies with clinical trials of CAR T cell therapy in solid tumors mostly falling short of expectations. One potential pitfall of CAR T functionality in this setting may be concomitant polychemotherapy (CTX), which remains standard-of-care in PDAC patients and will have been applied when CAR T generation takes place. Therefore, a better understanding of the implications of different CTX regimen on T cell functionality is needed to guide potential combinations of CAR T cell therapy and CTX in PDAC.Methods We generated patient-derived, 2nd generation anti-Mesothelin (MSLN) directed CAR T cells from 30 PDAC patients subjected to one of five CTX regimens (Gemcitabine, Gemcitabine/Nab-paclitaxel, Gemcitabine/Nab-paclitaxel/Azacitidine, FOLFOX or FOLFIRINOX) at our center after informed consent. In vitro analysis of CAR T products was performed at three distinct timepoints: before CTX (TP1), after first (TP2) and after multiple cycles of CTX (TP3). The analysis included phenotypic profiling of T cells and assessment of successful CAR T cell generation and expansion by flow cytometry. Additionally, CAR T anti-tumor capacity was assessed via cytokine release assays and luciferase and xCELLigence-based cytotoxicity readouts after co-culture with a PDAC cell line. Healthy donor (HD) samples served as assay validations.Results We could demonstrate successful generation of anti-MSLN CAR T cells from patient peripheral blood mononuclear cells (PBMC) with adequate yield and CAR transduction rate. While overall CTX exposure resulted in decreased T cell counts, no relevant impairment of T cell viability was noted. Baseline phenotype of isolated T cells did not notably change across timepoints and CTX regimen, except for a slight reduction in CD8+ memory subset formation. T cells of patients receiving Gemcitabine/Nab-Paclitaxel regimen showed lower CAR transduction efficacy and expansion rate as compared to T cells of patients receiving FOLFOX and FOLFIRINOX based therapy, indicating an impact on T cell fitness through Gemcitabine/Nab-Paclitaxel regimen.Conclusion Overall, our findings show that CAR T cells can effectively be generated from PDAC patients with prior or concomitant CTX treatment, though certain regimen may impact cellular fitness and expansion potential of CAR T products. These result, while they may vary between entities, underscore the necessity for further investigations optimizing combinations of CAR T cell application and chemotherapy in solid tumors.