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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.


ABSTRACT: The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

SUBMITTER: Le DT 

PROVIDER: S-EPMC5576142 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

Le Dung T DT   Durham Jennifer N JN   Smith Kellie N KN   Wang Hao H   Bartlett Bjarne R BR   Aulakh Laveet K LK   Lu Steve S   Kemberling Holly H   Wilt Cara C   Luber Brandon S BS   Wong Fay F   Azad Nilofer S NS   Rucki Agnieszka A AA   Laheru Dan D   Donehower Ross R   Zaheer Atif A   Fisher George A GA   Crocenzi Todd S TS   Lee James J JJ   Greten Tim F TF   Duffy Austin G AG   Ciombor Kristen K KK   Eyring Aleksandra D AD   Lam Bao H BH   Joe Andrew A   Kang S Peter SP   Holdhoff Matthias M   Danilova Ludmila L   Cope Leslie L   Meyer Christian C   Zhou Shibin S   Goldberg Richard M RM   Armstrong Deborah K DK   Bever Katherine M KM   Fader Amanda N AN   Taube Janis J   Housseau Franck F   Spetzler David D   Xiao Nianqing N   Pardoll Drew M DM   Papadopoulos Nickolas N   Kinzler Kenneth W KW   Eshleman James R JR   Vogelstein Bert B   Anders Robert A RA   Diaz Luis A LA  

Science (New York, N.Y.) 20170608 6349


The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiogra  ...[more]

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