Antiangiogenic Agents Can Increase Lymphocyte Infiltration into Tumor and Enhance the Effectiveness of Adoptive Immunotherapy of Cancer

Abstract Adoptive cell transfer (ACT)–based immunotherapies can mediate objective cancer regression in animalmodels and in up to 70% of patients with metastatic melanoma; however, it remains unclear whether thetumor vasculature impedes the egress of tumor-specific T cells, thus hindering this immunotherapy. Disrup-tion of the proangiogenic interaction of vascular endothelial growth factor (VEGF) with its receptor (VEGFR-2)has been reported to “normalize” tumor vasculature, enhancing the efficacy of chemotherapeutic agents byincreasing their delivery to the tumor intersitium. We thus sought to determine whether disrupting VEGF/VEGFR-2 signaling could enhance the effectiveness of ACT in a murine cancer model. The administration ofan antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16melanoma (P = 0.009) and improve survival (P = 0.003). Additive effects of an antibody against VEGFR-2 inconjunction with ACT were seen in this model (P = 0.013). Anti-VEGF, but not anti–VEGFR-2, antibody sig-nificantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculaturethrough disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells intothe tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration ofcombining antiangiogenic agents with ACT for the treatment of patients with cancer.