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posted on 2023-03-30, 23:49 authored by Zachary S. Morris, Emily I. Guy, David M. Francis, Monica M. Gressett, Lauryn R. Werner, Lakeesha L. Carmichael, Richard K. Yang, Eric A. Armstrong, Shyhmin Huang, Fariba Navid, Stephen D. Gillies, Alan Korman, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel The time-sensitivity of combined radiation and hu14.18-IL2 is not observed with radiation and hu14.18K322A and radiation induces a dose-dependent increase in Fas/CD95 expression.
Funding
ASTRO Resident Seed Grant, Sari Zirbel Memorial Fund
NIH
Midwest Athletes for Childhood Cancer, Crawdaddy Foundation, Evan Dunbar Foundation, Hyundai Hope on Wheels Foundation, UW ICTR
Stand Up To Cancer—St. Baldrick's Foundation Pediatric Dream Team Translational Research
Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research
History
ARTICLE ABSTRACT
Interest in combining radiotherapy and immune checkpoint therapy is growing rapidly. In this study, we explored a novel combination of this type to augment antitumor immune responses in preclinical murine models of melanoma, neuroblastoma, and head and neck squamous cell carcinoma. Cooperative effects were observed with local radiotherapy and intratumoral injection of tumor-specific antibodies, arising in part from enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). We could improve this response by combining radiation with intratumoral injection of an IL2-linked tumor-specific antibody (termed here an immunocytokine), resulting in complete regression of established tumors in most animals associated with a tumor-specific memory T-cell response. Given the T-cell response elicited by combined local radiation and intratumoral immunocytokine, we tested the potential benefit of adding this treatment to immune checkpoint blockade. In mice bearing large primary tumors or disseminated metastases, the triple-combination of intratumoral immunocytokine, radiation, and systemic anti–CTLA-4 improved primary tumor response and animal survival compared with combinations of any two of these three interventions. Taken together, our results show how combining radiation and intratumoral immunocytokine in murine tumor models can eradicate large tumors and metastases, eliciting an in situ vaccination effect that can be leveraged further by T-cell checkpoint blockade, with immediate implications for clinical evaluation. Cancer Res; 76(13); 3929–41. ©2016 AACR.
