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

Dung Le, Jennifer Uram, Kellie Smith, Hao Wang, Bjarne R. Bartlett, Laveet K. Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S. Luber, Fay Wong, Nilofer Azad, Agnieszka A. Rucki, Daniel Laheru, Ross C Donehower, Atif Zaheer, George A. Fisher, Todd S. Crocenzi, James J. Lee, Tim F. GretenAustin G. Duffy, Kristen K. Ciombor, Aleksandra D. Eyring, Bao H. Lam, Andrew Joe, S. Peter Kang, Matthias Holdhoff, Liudmila V Danilova, Leslie Cope, Christian Meyer, Shibin Zhou, Richard M. Goldberg, Deborah Kay Armstrong, Katherine Bever, Amanda Nickles Nickles Fader, Janis M Taube, Franck Housseau, David Spetzler, Nianqing Xiao, Andrew Mark Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, James Eshleman, Bert Vogelstein, Robert A Anders, Luis A. Diaz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)409-413
Number of pages5
JournalScience
Volume357
Issue number6349
DOIs
StatePublished - Jul 28 2017

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Neoplasms
DNA Mismatch Repair
Disease-Free Survival
Turcot syndrome
Colorectal Neoplasms
Clone Cells
Genome
T-Lymphocytes
Mutation
Survival
Antibodies

ASJC Scopus subject areas

  • Medicine(all)
  • General

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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. / Le, Dung; Uram, Jennifer; Smith, Kellie; Wang, Hao; Bartlett, Bjarne R.; Aulakh, Laveet K.; Lu, Steve; Kemberling, Holly; Wilt, Cara; Luber, Brandon S.; Wong, Fay; Azad, Nilofer; Rucki, Agnieszka A.; Laheru, Daniel; Donehower, Ross C; Zaheer, Atif; Fisher, George A.; Crocenzi, Todd S.; Lee, James J.; Greten, Tim F.; Duffy, Austin G.; Ciombor, Kristen K.; Eyring, Aleksandra D.; Lam, Bao H.; Joe, Andrew; Kang, S. Peter; Holdhoff, Matthias; Danilova, Liudmila V; Cope, Leslie; Meyer, Christian; Zhou, Shibin; Goldberg, Richard M.; Armstrong, Deborah Kay; Bever, Katherine; Nickles Fader, Amanda Nickles; Taube, Janis M; Housseau, Franck; Spetzler, David; Xiao, Nianqing; Pardoll, Andrew Mark; Papadopoulos, Nickolas; Kinzler, Kenneth W; Eshleman, James; Vogelstein, Bert; Anders, Robert A; Diaz, Luis A.

In: Science, Vol. 357, No. 6349, 28.07.2017, p. 409-413.

Research output: Contribution to journalArticle

Le, D, Uram, J, Smith, K, Wang, H, Bartlett, BR, Aulakh, LK, Lu, S, Kemberling, H, Wilt, C, Luber, BS, Wong, F, Azad, N, Rucki, AA, Laheru, D, Donehower, RC, Zaheer, A, Fisher, GA, Crocenzi, TS, Lee, JJ, Greten, TF, Duffy, AG, Ciombor, KK, Eyring, AD, Lam, BH, Joe, A, Kang, SP, Holdhoff, M, Danilova, LV, Cope, L, Meyer, C, Zhou, S, Goldberg, RM, Armstrong, DK, Bever, K, Nickles Fader, AN, Taube, JM, Housseau, F, Spetzler, D, Xiao, N, Pardoll, AM, Papadopoulos, N, Kinzler, KW, Eshleman, J, Vogelstein, B, Anders, RA & Diaz, LA 2017, 'Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade', Science, vol. 357, no. 6349, pp. 409-413. https://doi.org/10.1126/science.aan6733
Le, Dung ; Uram, Jennifer ; Smith, Kellie ; Wang, Hao ; Bartlett, Bjarne R. ; Aulakh, Laveet K. ; Lu, Steve ; Kemberling, Holly ; Wilt, Cara ; Luber, Brandon S. ; Wong, Fay ; Azad, Nilofer ; Rucki, Agnieszka A. ; Laheru, Daniel ; Donehower, Ross C ; Zaheer, Atif ; Fisher, George A. ; Crocenzi, Todd S. ; Lee, James J. ; Greten, Tim F. ; Duffy, Austin G. ; Ciombor, Kristen K. ; Eyring, Aleksandra D. ; Lam, Bao H. ; Joe, Andrew ; Kang, S. Peter ; Holdhoff, Matthias ; Danilova, Liudmila V ; Cope, Leslie ; Meyer, Christian ; Zhou, Shibin ; Goldberg, Richard M. ; Armstrong, Deborah Kay ; Bever, Katherine ; Nickles Fader, Amanda Nickles ; Taube, Janis M ; Housseau, Franck ; Spetzler, David ; Xiao, Nianqing ; Pardoll, Andrew Mark ; Papadopoulos, Nickolas ; Kinzler, Kenneth W ; Eshleman, James ; Vogelstein, Bert ; Anders, Robert A ; Diaz, Luis A. / Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. In: Science. 2017 ; Vol. 357, No. 6349. pp. 409-413.
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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.",
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T1 - Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

AU - Le, Dung

AU - Uram, Jennifer

AU - Smith, Kellie

AU - Wang, Hao

AU - Bartlett, Bjarne R.

AU - Aulakh, Laveet K.

AU - Lu, Steve

AU - Kemberling, Holly

AU - Wilt, Cara

AU - Luber, Brandon S.

AU - Wong, Fay

AU - Azad, Nilofer

AU - Rucki, Agnieszka A.

AU - Laheru, Daniel

AU - Donehower, Ross C

AU - Zaheer, Atif

AU - Fisher, George A.

AU - Crocenzi, Todd S.

AU - Lee, James J.

AU - Greten, Tim F.

AU - Duffy, Austin G.

AU - Ciombor, Kristen K.

AU - Eyring, Aleksandra D.

AU - Lam, Bao H.

AU - Joe, Andrew

AU - Kang, S. Peter

AU - Holdhoff, Matthias

AU - Danilova, Liudmila V

AU - Cope, Leslie

AU - Meyer, Christian

AU - Zhou, Shibin

AU - Goldberg, Richard M.

AU - Armstrong, Deborah Kay

AU - Bever, Katherine

AU - Nickles Fader, Amanda Nickles

AU - Taube, Janis M

AU - Housseau, Franck

AU - Spetzler, David

AU - Xiao, Nianqing

AU - Pardoll, Andrew Mark

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W

AU - Eshleman, James

AU - Vogelstein, Bert

AU - Anders, Robert A

AU - Diaz, Luis A.

PY - 2017/7/28

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N2 - 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.

AB - 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.

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