title: Radiation-Induced Enhancement of Antitumor T-cell Immunity by VEGF-Targeted 4-1BB Costimulation.
abstract: 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.Cancer Res; 77(6); 1310-21. ©2017 AACR.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Brett
authors.initials: B
authors.lastname: Schrand
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Verma
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Agata
authors.initials: A
authors.lastname: Levay
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Shradha
authors.initials: S
authors.lastname: Patel
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Iris
authors.initials: I
authors.lastname: Castro
authors.affiliation: Department of Radiation Oncology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Benaduce
authors.affiliation: Department of Radiation Oncology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Randall
authors.initials: R
authors.lastname: Brenneman
authors.affiliation: Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Oliver
authors.initials: O
authors.lastname: Umland
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
authors.affiliation: Department of Radiation Oncology, Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida. aishkanian@med.miami.edu.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ishkanian
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D005720:Gamma Rays / Q000009:adverse effects*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000209:etiology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D052157:Aptamers, Nucleotide; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse