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

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 15; pp. 6171 - 6180
• Main Authors: SHRIMALI, Rajeev K, ZHIYA YU, THEORET, Marc R, CHINNASAMY, Dhanalakshmi, RESTIFO, Nicholas P, ROSENBERG, Steven A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2010
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antineoplastic agents; Bevacizumab; Biological and medical sciences; Combined Modality Therapy; Epitopes, T-Lymphocyte - immunology; gp100 Melanoma Antigen; Immunotherapy, Adoptive - methods; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pharmacology. Drug treatments; Skin Neoplasms - immunology; Skin Neoplasms - therapy; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - immunology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - immunology; Whole-Body Irradiation; Efficiency; Infiltration; Malignant tumor; Antiangiogenic agent; Adoptive immunization; Lymphocyte; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-0153

Adoptive cell transfer (ACT)-based immunotherapies can mediate objective cancer regression in animal models and in up to 70% of patients with metastatic melanoma; however, it remains unclear whether the tumor vasculature impedes the egress of tumor-specific T cells, thus hindering this immunotherapy. Disruption 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 by increasing 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 of an antibody against mouse VEGF synergized with ACT to enhance inhibition of established, vascularized, B16 melanoma (P = 0.009) and improve survival (P = 0.003). Additive effects of an antibody against VEGFR-2 in conjunction with ACT were seen in this model (P = 0.013). Anti-VEGF, but not anti-VEGFR-2, antibody significantly increased infiltration of transferred cells into the tumor. Thus, normalization of tumor vasculature through disruption of the VEGF/VEGFR-2 axis can increase extravasation of adoptively transferred T cells into the tumor and improve ACT-based immunotherapy. These studies provide a rationale for the exploration of combining antiangiogenic agents with ACT for the treatment of patients with cancer.