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 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.

• Authors: Rajeev K Shrimali, Zhiya Yu, Marc R Theoret, Dhanalakshmi Chinnasamy, Nicholas P Restifo, Steven A Rosenberg
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 15 Pg. 6171-80 (Aug 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20631075 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• DC101 monoclonal antibody
• Epitopes, T-Lymphocyte
• Membrane Glycoproteins
• Pmel protein, mouse
• Vascular Endothelial Growth Factor A
• gp100 Melanoma Antigen
• Bevacizumab
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Bevacizumab
• Combined Modality Therapy
• Epitopes, T-Lymphocyte (immunology)
• Immunotherapy, Adoptive (methods)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Melanoma, Experimental (immunology, therapy)
• Membrane Glycoproteins (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Skin Neoplasms (immunology, therapy)
• T-Lymphocytes (drug effects, immunology)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, immunology)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, immunology)
• Whole-Body Irradiation
• gp100 Melanoma Antigen