Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Radiotherapy enhances systemic responses to anti-CTLA-4 antibodies in pre-clinical studies and in some melanoma patients, but its efficacy in inducing systemic responses against tumors unresponsive to CTLA-4 blockade remained uncertain. We evaluated the responses of non-irradiated metastases in non-small cell lung cancer (NSCLC) patients treated with radiotherapy to one metastasis and CTLA-4 blockade. Objective radiographic responses were observed in 33% of the patients who completed the treatment, and patients who achieved disease control had a significantly longer overall survival. Increased serum levels of interferon- after radiation and the early expansion and contraction of T cell clonotypes in peripheral blood were the strongest predictors of response, confirming mechanistic data in pre-clinical studies. Functional analysis in a responding patient showed the rapid in vivo expansion of CD8 T cells specific for a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that radiation exposes immunogenic mutations to the immune system.