Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1,2,3, 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 tumor4,5,6. 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.
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The data reported are tabulated in the manuscript and supplementary figures and tables, and Supplementary Dataset 2 and 3. Raw data for soluble markers and flow cytometry are available in Supplementary Dataset 1. The raw TCR sequence data have been deposited into the ImmuneACCESS project repository of the Adaptive Biotechnology database (https://doi.org/10.21417/B7BW6X). WES and RNA-seq data have been deposited at the NCBI Sequence Read Archive (accession number SRP136187; http://www.ncbi.nlm.nih.gov/bioproject/439205).
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We to acknowledge J. Goldberg for the initial design of the clinical trial, K. Pilones for assistance with DNA preparation, L. Chriboga for help with immunohistochemistry, D. Morrison for blood processing, and the NYULH Genome Technology Center (GTC) technical personnel for sequencing. We thank S. Chandraseckhar for data management, M. Fenton-Kerimian for patient care, and G. Inghirami for providing the PDX mice. We thank Bristol Meyer Squibb, New York, NY, USA, for providing ipilimumab for this research study. We are indebted to G. Koretzky for insightful discussion and review of the manuscript. The immunological studies were funded by NCI grants no. R01CA198533 and no. R01CA201246 (to S.D.). The NYU Experimental Pathology Immunohistochemistry Core Laboratory and the GTC are partially supported by the Cancer Center support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center, NYULH. E.W. is supported by a DOD W81XWH-17-1-0029 post-doctoral fellowship. S.G. acknowledges the Human Immune Monitoring Center at Mount Sinai and Cancer Center support grant P30CA196521. L.F.A. was funded by a Friends for Life Neuroblastoma Fellowship and K.W.W. was supported by National Cancer Institute (NCI) grant no. R01 CA173750.
Bristol Meyer Squibb did not have any role in the design, data collection and analysis, interpretation of results and preparation of the manuscript. Potential conflicts of interest: Full-time employment and equity ownership at Adaptive Biotechnologies Corporation (R.O.E.). Prior honorarium for consulting from Third Rock Ventures/Neon Therapeutics, B4CC, OncoMed, Merck, and research funding from Agenus, Bristol Meyer Squibb, Genentech, Pfizer, Janssen R&D, Immune Design (S.G.). Service on Scientific Advisory Board of Lytix Biopharma, prior honorarium for consulting/speaker from AstraZeneca, AbbVie Inc., Cytune Pharma, EMD Serono, Eisai Inc., Regeneron, Ventana Medical Systems, Inc. Research grants from Nanobiotix, and Lytix Biopharma (S.D.). Prior honorarium for consulting/speaker from Sanofi, AstraZeneca, Merck, Regeneron, Bayer, Serono/Merck, and research funding from Janssen R&D, Varian, Merck, Bristol Meyer Squibb (for a different study) (S.C.F.). Service on Scientific Advisory Board of Nextech, T-scan and TCR2, consultancy for Novartis, research funding from Astellas, Bristol-Myers Squibb and Novartis (not related to the topic of this mansucript) (K.W.W.).
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Supplementary Figures 1–6 and Supplementary Tables 1–9
Raw data for all soluble markers and circulating lymphocytes analyzed
Summary tables of all soluble markers and circulating immune cell subsets showing significant differences at baseline in responding and nonresponding patients and/or showing significant changes during treatment
Summary tables showing the results of CTLA-4 expression analysis on circulating conventional and regulatory CD4 T cells and CD8 T cells at baseline and during treatment
List of variants identified by WES in the tumours of patients #4, 32, 36, and 38
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Formenti, S.C., Rudqvist, NP., Golden, E. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 24, 1845–1851 (2018). https://doi.org/10.1038/s41591-018-0232-2
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