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Nat Med. 2018 Dec;24(12):1845-1851. doi: 10.1038/s41591-018-0232-2. Epub 2018 Nov 5.

Radiotherapy induces responses of lung cancer to CTLA-4 blockade.

Author information

1
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. formenti@med.cornell.edu.
2
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA.
3
Department of Radiation Oncology, University of California, San Francisco, CA, USA.
4
Department of Radiation Oncology, New York University School of Medicine, New York, NY, USA.
5
Department of Radiology, New York University School of Medicine, New York, NY, USA.
6
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
7
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
8
Department of Pathology, New York University School of Medicine, New York, NY, USA.
9
Genome Technology Center, Division of Advanced research Technologies, NYU Langone Health, New York, NY, USA.
10
Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
11
Adaptive Biotechnologies, Seattle, WA, USA.
12
Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA.
13
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
14
Department of Medicine, New York University School of Medicine, New York, NY, USA.
15
Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu.
16
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu.

Abstract

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1-3, 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 tumor4-6. The latter is essential for achieving abscopal responses in murine cancers6. 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 chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β 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.

PMID:
30397353
PMCID:
PMC6286242
[Available on 2019-05-05]
DOI:
10.1038/s41591-018-0232-2

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