Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-03, Vol.77 (6), p.1310-1321
• Main Authors: Schrand, Brett, Verma, Bhavna, Levay, Agata, Patel, Shradha, Castro, Iris, Benaduce, Ana Paula, Brenneman, Randall, Umland, Oliver, Yagita, Hideo, Gilboa, Eli, Ishkanian, Adrian
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Aptamers; Aptamers, Nucleotide - pharmacology; Cancer; CTLA-4 protein; Drug delivery; Gamma Rays - adverse effects; Humans; Immune checkpoint; Immunoglobulins; Immunomodulation; Immunosuppressive agents; Immunotherapy; Inflammation; Lesions; Lymphocytes T; Mice; Mice, Inbred BALB C; Molecular Targeted Therapy; Neoplasms, Experimental - etiology; Neoplasms, Experimental - prevention & control; Oligonucleotides; PD-1 protein; Radiation; Radiation therapy; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - radiation effects; Toxicity; Tumor Cells, Cultured; Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-2105

Radiotherapy can elicit systemic immune control of local tumors and distant nonirradiated tumor lesions, known as the abscopal effect. Although this effect is enhanced using checkpoint blockade or costimulatory antibodies, objective responses remain suboptimal. As radiotherapy can induce secretion of VEGF and other stress products in the tumor microenvironment, we hypothesized that targeting immunomodulatory drugs to such products will not only reduce toxicity but also broaden the scope of tumor-targeted immunotherapy. Using an oligonucleotide aptamer platform, we show that radiation-induced VEGF-targeted 4-1BB costimulation potentiated both local tumor control and abscopal responses with equal or greater efficiency than 4-1BB, CTLA-4, or PD1 antibodies alone. Although 4-1BB and CTLA-4 antibodies elicited organ-wide inflammatory responses and tissue damage, VEGF-targeted 4-1BB costimulation produced no observable toxicity. These findings suggest that radiation-induced tumor-targeted immunotherapy can improve the therapeutic index and extend the reach of immunomodulatory agents. .