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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 14, 2017
- Source ID
- 10.1158/0008-5472.can-16-2105
Entities
People
- Adrian Ishkanian
- Agata Levay
- Ana Paula Benaduce
- Bhavna Verma
- Brett Schrand
- Eli Gilboa
- Hideo Yagita
- Iris Castro
- Oliver Umland
- Randall Brenneman
- Shradha Patel
Organizations
- Congressionally Directed Medical Research Programs
- Juntendo University
- University of Miami