TY - JOUR
T1 - Radiotherapy induces responses of lung cancer to CTLA-4 blockade
AU - Formenti, Silvia C.
AU - Rudqvist, Nils Petter
AU - Golden, Encouse
AU - Cooper, Benjamin
AU - Wennerberg, Erik
AU - Lhuillier, Claire
AU - Vanpouille-Box, Claire
AU - Friedman, Kent
AU - Ferrari de Andrade, Lucas
AU - Wucherpfennig, Kai W.
AU - Heguy, Adriana
AU - Imai, Naoko
AU - Gnjatic, Sacha
AU - Emerson, Ryan O.
AU - Zhou, Xi Kathy
AU - Zhang, Tuo
AU - Chachoua, Abraham
AU - Demaria, Sandra
N1 - Publisher Copyright:
© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41591-018-0232-2
DO - 10.1038/s41591-018-0232-2
M3 - Article
C2 - 30397353
AN - SCOPUS:85056171521
SN - 1078-8956
VL - 24
SP - 1845
EP - 1851
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -