In a pilot trial, 39 patients with chemotherapy-refractory metastatic NSCLC were treated with ipilimumab and local radiotherapy to one metastasis. Objective response was observed in 7 patients (2 CR, 5 PR) and 5 patients had stable disease. Treatment-induced increase in serum IFNβ and early changes in TCR clonal dynamics in the blood correlated with abscopal response. In one responding patient, there was a rapid expansion of two CD8+ T cell clones recognizing a neoantigen from a mutated gene that was upregulated by radiation and present in two brain metastases.

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.

Author Info: (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

Author Info: (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, Weill Cornell Medicine, New York, NY, USA. 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 Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (6) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (7) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. (8) Department of Radiology, New York University School of Medicine, New York, NY, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. (11) Department of Pathology, New York University School of Medicine, New York, NY, USA. Genome Technology Center, Division of Advanced research Technologies, NYU Langone Health, New York, NY, USA. (12) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (13) Tisch Cancer Institute, Hematology/Oncology, Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (14) Adaptive Biotechnologies, Seattle, WA, USA. (15) Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, NY, USA. (16) Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA. (17) Department of Medicine, New York University School of Medicine, New York, NY, USA. (18) Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. szd3005@med.cornell.edu.

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