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.