Journal Article

Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Zhou, Xi Kathy, Vanpouille-Box, Claire, Ferrari de Andrade, Lucas, Lhuillier, Claire, Imai, Naoko, Chachoua, Abraham, Zhang, Tuo, Demaria, Sandra, Wucherpfennig, Kai W., Gnjatic, Sacha, Friedman, Kent, Formenti, Silvia C., Golden, Encouse, Heguy, Adriana, Cooper, Benjamin, Rudqvist, Nils-Petter, Emerson, Ryan O., Wennerberg, Erik

2018

Overview

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-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. Radiotherapy-induced abscopal responses enhance the efficacy of anti-CTLA-4 in patients with non-small-cell lung cancer.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059 / 631/67/1612 / 631/67/580 / 692/308/2779/109 / 692/308/575 / Aged / Aged, 80 and over / Analysis / Antibodies / Antibodies, Monoclonal - administration & dosage / Anticancer properties / Biological response modifiers / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer metastasis / Cancer Research / Care and treatment / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - radiation effects / Cell activation / Cell Line, Tumor / Chemotherapy / Combined Modality Therapy / CTLA-4 Antigen - antagonists & inhibitors / CTLA-4 Antigen - immunology / CTLA-4 protein / Data processing / Disease control / Drug Resistance, Neoplasm - radiation effects / Female / Functional analysis / Genes / Genetic aspects / Humans / Immune response / Immune system / Immunogenicity / Infectious Diseases / Interferon / Ipilimumab - administration & dosage / Letter / Lung cancer / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Lung Neoplasms - radiotherapy / Lung Neoplasms - therapy / Lymphocytes / Lymphocytes T / Male / Medical research / Medical schools / Metabolic Diseases / Metastases / Middle Aged / Molecular Medicine / Mutation / Neoantigens / Neurosciences / Non-small cell lung cancer / Non-small cell lung carcinoma / Patients / Radiation (Physics) / Radiation effects / Radiation therapy / Radiotherapy / T cells / Treatment outcome / Tumor antigens / Tumors