Radiation-induced enhancement of antitumor T-cell immunity by VEGF-targeted 4-1BB costimulation

Brett Schrand, Bhavna Verma, Agata Levay, Shradha Patel, Iris Castro, Ana Paula Benaduce, Randall Brenneman, Oliver Umland, Hideo Yagita, Eli Gilboa, Adrian Ishkanian

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1310-1321
Number of pages12
JournalCancer Research
Volume77
Issue number6
DOIs
StatePublished - Mar 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schrand, B., Verma, B., Levay, A., Patel, S., Castro, I., Benaduce, A. P., Brenneman, R., Umland, O., Yagita, H., Gilboa, E., & Ishkanian, A. (2017). Radiation-induced enhancement of antitumor T-cell immunity by VEGF-targeted 4-1BB costimulation. Cancer Research, 77(6), 1310-1321. https://doi.org/10.1158/0008-5472.CAN-16-2105