Radiotherapy induces responses of lung cancer to CTLA-4 blockade

By S. Formenti, N. Rudqvist, E. Golden, B. Cooper, E. Wennerberg, C. Lhuillier, C. Vanpouille‐Box, K. Friedman, Lucas Ferrari de Andrade, K. Wucherpfennig and 8 more. Nature Medicine, 2018

797 citations recorded by the source corpus.

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1–3, 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 tumor4–6. The latter is essential for achieving abscopal responses in murine cancers6. 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 chemotherapy7,8. 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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/bbd93e181358a444c017610c17433a43e136d741

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Citations in the corpus

Neoantigens: promising targets for cancer therapy (2023, background): “Peptides derived from mutant KPNA2 trigger neoantigen-reactive CD8 T cells and induce IFNγ production, which may trigger antigen spread.(472,473) In addition, radiation can enhance the levels of existing peptide presentation by increasing the surface expression of MHC-I on tumor cells.”
Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (2020, background): “Time to first recurrence, median (range), mo 22 (9-42) 22 (9-51)”