Abstract LB-B003: Exploiting lymphangiogenesis to boost anti-tumor T cell responses in B cell lymphoma

Abstract In diffuse large B-cell lymphoma (DLBCL), the large tumor burden in secondary lymphoid organs, coupled with lymphodepletion caused by current therapies like R-CHOP and induced prior to CAR T-cell therapy, all cause profound immunosuppression, contributing to high relapse rates and infectious complications. Thus, combination approaches that boost host immunity may improve efficacy. Lymphatic-rich DLBCL subtypes are often overlooked in studies, even though DLBCL patients exhibit superior survival rates when tumors express high levels of lymphangiogenic gene signatures including vascular endothelial growth factor-C (VEGF-C), suggesting that local lymphatics support effective anti-tumor immune responses in DLBCL patients. We investigated how lymphangiogenesis influences T cell activation in the context of lymphoma. First, we analyzed the gene expression data from patients in the NCICCR-DLBCL database and found that high levels of VEGF-C correlated with better prognosis, and identified strong correlations between VEGF-C expression and tumor-infiltrating lymphocyte signatures. Next, to explore lymphatic-immune cell interactions, we developed an in vivo vaccination model using lethally irradiated VEGF-C-expressing cells combined with lymphoma antigens (VC Vax), which we previously developed in the context of melanoma. Since abundance in TILs and cytotoxic TILs pre-treatment associates with improved overall survival post CAR T-cell therapy, we hypothesized that CAR T cells could be primed and expanded at the VC Vax site without lymphodepletion, preserving endogenous T cells that might synergize with CAR T cells. We therefore combined VC Vax with aCD19 CAR T cells and evaluated T cell functions at the vaccination site and systemically by flow cytometry and restimulation assays. CAR T-cells preferentially accumulated at the vaccination site, and VEGF-C expression enhanced dendritic cell recruitment as well as proliferation and activation of endogenous T cells locally. Lymphocyte egress blockade via FTY720 did not abrogate local T cell activation, supporting in situ T cell education within the vaccination site microenvironment. VC Vax increased granzyme B expression in circulating T cells and in ex vivo restimulated splenic CD8 T cells in a lymphocyte egress-dependent manner, suggesting the differentiation of systemic effector functions seeded from the vaccine site. We thus hypothesized that endogenous T cells educated at the vaccination site could provide systemic antitumor immunity. Indeed, vaccinated mice conferred protection against primary tumor challenge and two subsequent lymphoma rechallenges, indicating durable systemic immunity. These data suggest that combining lymphangiogenesis-inducing whole cell vaccines with CAR-T cell therapy can promote transferred T cell-engraftment and prime endogenous bystander T cells, providing a novel strategy to enhance overall efficacy of CAR T-cells in B-cell lymphoma while preserving overall immune competence. Citation Format: Emily(Qinyue) Liu, Thomas Wang, Melody A. Swartz. Exploiting lymphangiogenesis to boost anti-tumor T cell responses in B cell lymphoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-B003.