Journal
NATURE MEDICINE
Volume 24, Issue 12, Pages 1845-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-018-0232-2
Keywords
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Funding
- NCI [R01CA198533, R01CA201246]
- Cancer Center support grant at the Laura and Isaac Perlmutter Cancer Center, NYULH [P30CA016087]
- DOD [W81XWH-17-1-0029]
- Cancer Center support grant [P30CA196521]
- Friends for Life Neuroblastoma Fellowship
- National Cancer Institute (NCI) [R01 CA173750]
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Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma(1-3), but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor(4-6). The latter is essential for achieving abscopal responses in murine cancers(6). The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy(7,8). Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-beta after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.
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