Radiotherapy-induced Responses Enhance the Efficacy of Anti-CTLA4 Therapy in Chemo-refractory Metastatic NSCLC

Abscopal responses observed in tumours unresponsive to CTLA-4 blockade
09 Nov 2018

In a letter published on 5 November 2018 in the Nature Medicine, Silvia Formenti of the Department of Radiation Oncology, Weill Cornell Medicine, New York, USA and colleagues reported that radiotherapy and CTLA4 blockade induced systemic antitumour T cells in chemo-refractory metastatic non-small cell lung cancer (NSCLC), the setting where anti-CTLA4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy.

The authors wrote in a study background that radiotherapy enhances systemic responses to anti-CTLA4 antibodies in preclinical studies and in some patients with melanoma. However, its efficacy in inducing abscopal responses against tumours unresponsive to CTLA4 blockade remained uncertain.

In particular, radiotherapy promotes the activation of antitumour T cells. Such effect is dependent on type I interferon induction in the irradiated tumour. The latter is essential for achieving abscopal responses in murine cancers. But the mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA4 blockade remain unclear.

In the study by Formenti et al. objective responses were observed in 18% of enrolled patients, and 31% had disease control. Furthermore, increased serum interferon-β after radiotherapy 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 recognising 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.

Bristol Meyer Squibb provided ipilimumab for this research study, however it did not have any role in the design, data collection and analysis, interpretation of results and preparation of the manuscript. The immunological studies were funded by US National Cancer Institute grants. Multiple support grants from participating cancer centres and fellowships were acknowledged in the report as well. 

Reference

Formenti SC, Rudqvist NP, Golden E, et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nature Medicine; Piblished online 5 November 2018. doi: 10.1038/s41591-018-0232-2.

Last update: 09 Nov 2018

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