Anti-Angiogenic Therapy Improves Anti-Tumor Efficacy of Bispecific-Armed T cell Immunotherapy against Solid Tumors

초록

Background: Success of T cell immunotherapy relies on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors. The efficacy of T cell engaging bispecific antibody (T-BsAb) treatment depends on the successful trafficking and cytolytic activity of T cells in solid tumors. Targeting tumor vasculature using anti-angiogenic therapies could improve anti-tumor efficacy of BsAb-based T cell immunotherapy. Methods: Anti-human VEGF (bevacizumab, BVZ) or anti-mouse VEGFR2 antibody (DC101) was combined with BsAb-armed T cell immunotherapy. Ex vivo armed T cells (EATs) with anti-GD2, anti-HER2, or anti-glypican3 (GPC3) IgG-[L]-scFv platformed BsAb were tested. In vivo anti-tumor response and intratumoral T cell infiltration were evaluated using tumor-xenografted mouse models. VEGF expression on human cancer cell lines was analyzed by flow cytometry, and VEGF levels in mouse serum were measured using VEGF Quantikine ELISA Kit. Tumor infiltrating lymphocytes (TILs) were evaluated using flow cytometry of tumor lysates and by in vivo bioluminescence; both TILs and tumor vasculature were studied using immunohistochemistry. Results:. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1 to 8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior anti-tumor effects in multiple tumor models without added toxicities. Conclusions: Anti-angiogenic therapies significantly increased HEVs in the TME and cytotoxic CD8(+) T cell infiltration, significantly improving the therapeutic efficacy of EAT therapy, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies.