Radiotherapy May Sensitize to CTLA4 Blockade in Patients with NSCLC

Radiation therapy can activate antitumor T cells to promote a systemic (abscopal) response in untreated lesions. This abscopal effect depends on the induction of type I interferon in the irradiated tumor. In a patient with non–small cell lung cancer (NSCLC) treated with a combination of radiation therapy and the anti-CTLA4 antibody ipilimumab, a complete and durable abscopal response was observed. However, the mechanisms underlying the abscopal response after treatment with radiation and ipilimumab have not been thoroughly investigated. In a phase II trial, Formenti and colleagues evaluated the safety and efficacy of radiation therapy in combination with ipilimumab in 39 patients with chemorefractory metastatic NSCLC (a population where anti-CLTA4 antibodies have limited efficacy alone or in combination with chemotherapy). Overall, 7 of 21 (33%) evaluable patients who completed 4 cycles of ipilimumab achieved an objective response, 2 complete and 5 partial responses, and 5 patients experienced stable disease, for a disease control rate of 31%. The median overall survival was 7.4 months and 13 months in patients who completed treatment. Analysis of circulating soluble markers and immune cells in the 21 evaluable patients revealed increased serum IFNβ after radiation in responding patients. Deep sequencing of the T-cell receptor (TCR) showed a more robust expansion of tumor-derived TCR clones in peripheral blood after radiation plus ipilimumab in responding patients. Combined increased IFNβ and TCR repertoire changes were most predictive of response to therapy. Functional analysis in a single responding patient demonstrated that radiotherapy plus ipilimumab promoted expansion of CD8⁺ T cells recognizing a KPNA2 neoantigen. KPNA2 is upregulated by radiation, suggesting that radiation may induce an abscopal response by inducing the expression of immunogenic mutations. These findings support further investigation of radiotherapy in combination with ipilimumab for the treatment of metastatic NSCLC, and provide a mechanism by which radiotherapy may enhance the antitumor immune response.

Formenti SC, Rudqvist NP, Golden E, Cooper B, Wennerberg E, Lhuillier C, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 2018 Nov 5 [Epub ahead of print].

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