Abstract 3982: FGFR1+ cancer-associated fibroblasts contribute to the failure of CAR-T cell therapy in B-cell lymphoma through the secretion of TGFβ

Abstract Despite significant advancements in chimeric antigen receptor (CAR) T-cell therapies targeting CD19 for relapsed B cell malignancies, over 50% of lymphoma patients do not achieve sustained remission. The roles of cancer-associated fibroblasts (CAF) in reprogramming lymphoma microenvironments and their relationship with CAR T-cell response are becoming increasingly evident. Evidence suggests that TGFβ-activated stromal gene signatures are enriched in immunosuppressive lymphoma microenvironments (LME) and in non-responder CAR T-cell patients (Cerchietti. Cancer Discovery 2021, Locke. Nature Medicine 2024). In previous studies using pre-clinical lymphoma models, we demonstrated that FGFR1 inhibition in CAFs can reverse extracellular matrix compositional changes and increase the secretion of several monocyte chemoattractant proteins, thereby promoting the infiltration of anti-lymphoma macrophages and inducing anti-tumor effect in FGFR1neg lymphoma cells (Di Siervi. Cancer Research 2024). We report now that FGFR1+ CAF are a consistent source of TGFβ. We discovered that TGFβ secretion in CAF is tightly regulated by FGFR1 activity. Genetic downregulation and pharmacological inhibition of FGFR1 (SSR128129E, FGFR1i) in three different activated fibroblast models led to a significant decrease in TGFβ transcription, expression, and secretion (p 0.005). We developed a patient-derived xenograft (PDX) model from a B-cell lymphoma patient refractory to CD19 CAR T cell therapy, that we use to test the effect of pharmacological FGFR1 inhibition to the anti-tumor effect of human CD19-CAR T cells. Compared to vehicle, FGFR1i significantly reduced circulating tumor cells and increased circulating CAR T-cells (p 0.005). These findings correlated with a reduced tumor burden and increased CAR T cell infiltration in the intrasplenic tumors.To further characterize CART-cell function, we analyzed exhaustion phenotype. We observed a significant reduction in exhausted CD4+ and CD8+ T-cell populations (PD1+ LAG3+) in the CART plus FGFR1i group (p 0.05). Moreover, mice treated with the combination exhibited improved overall survival compared to those treated with CAR T cells alone (p 0.05) or FGFR1i alone (p 0.05). To test whether these results were specific for CD19-CAR T cells, we conducted similar experiments using BAFFR-CAR-T cells. Consistently, the combination of BAFFR-CAR T cells and FGFR1i increased CAR T cell expansion (p 0.005), reduced T-cell exhaustion (p 0.05), and improved overall survival compared to FGFR1i (p 0.005) and CAR T cell therapy alone (p 0.005). In conclusion, our findings suggest that the multifactorial changes induced by FGFR1i rewire the immunosuppressive LME, enhancing CAR T-cell infiltration, expansion, and antitumor activity. Citation Format: Nicolas Di Siervi, Maria Victoria Revuelta, Giovanni Medico, Giorgio Ga. Inghirami, Leandro Cerchietti. FGFR1+ cancer-associated fibroblasts contribute to the failure of CAR-T cell therapy in B-cell lymphoma through the secretion of TGFβ abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3982.