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

Dung T. Le, Jennifer N. Durham, Kellie N. Smith, Hao Wang, Bjarne R. Bartlett, Laveet K. Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S. Luber, Fay Wong, Nilofer S. Azad, Agnieszka A. Rucki, Dan Laheru, Ross Donehower, Atif Zaheer, George A. Fisher, Todd S. Crocenzi, James J. Lee, Tim F. Greten & 26 others Austin G. Duffy, Kristen K. Ciombor, Aleksandra D. Eyring, Bao H. Lam, Andrew Joe, S. Peter Kang, Matthias Holdhoff, Ludmila Danilova, Leslie Cope, Christian Meyer, Shibin Zhou, Richard M. Goldberg, Deborah K. Armstrong, Katherine M. Bever, Amanda N. Fader, Janis Taube, Franck Housseau, David Spetzler, Nianqing Xiao, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, James R. Eshleman, Bert Vogelstein, Robert A. Anders, Luis A. Diaz

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages409-413
Number of pages5
JournalScience
Volume357
Issue number6349
DOIs
StatePublished - Jul 28 2017

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

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Le, D. T., Durham, J. N., Smith, K. N., Wang, H., Bartlett, B. R., Aulakh, L. K., ... Diaz, L. A. (2017). Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science, 357(6349), 409-413. DOI: 10.1126/science.aan6733

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. / Le, Dung T.; Durham, Jennifer N.; Smith, Kellie N.; Wang, Hao; Bartlett, Bjarne R.; Aulakh, Laveet K.; Lu, Steve; Kemberling, Holly; Wilt, Cara; Luber, Brandon S.; Wong, Fay; Azad, Nilofer S.; Rucki, Agnieszka A.; Laheru, Dan; Donehower, Ross; 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, Ludmila; Cope, Leslie; Meyer, Christian; Zhou, Shibin; Goldberg, Richard M.; Armstrong, Deborah K.; Bever, Katherine M.; Fader, Amanda N.; Taube, Janis; Housseau, Franck; Spetzler, David; Xiao, Nianqing; Pardoll, Drew M.; Papadopoulos, Nickolas; Kinzler, Kenneth W.; Eshleman, James R.; Vogelstein, Bert; Anders, Robert A.; Diaz, Luis A.

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

Research output: Research - peer-reviewArticle

Le, DT, Durham, JN, Smith, KN, Wang, H, Bartlett, BR, Aulakh, LK, Lu, S, Kemberling, H, Wilt, C, Luber, BS, Wong, F, Azad, NS, Rucki, AA, Laheru, D, Donehower, R, 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, L, Cope, L, Meyer, C, Zhou, S, Goldberg, RM, Armstrong, DK, Bever, KM, Fader, AN, Taube, J, Housseau, F, Spetzler, D, Xiao, N, Pardoll, DM, Papadopoulos, N, Kinzler, KW, Eshleman, JR, 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. DOI: 10.1126/science.aan6733
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Available from, DOI: 10.1126/science.aan6733
Le, Dung T. ; Durham, Jennifer N. ; Smith, Kellie N. ; Wang, Hao ; Bartlett, Bjarne R. ; Aulakh, Laveet K. ; Lu, Steve ; Kemberling, Holly ; Wilt, Cara ; Luber, Brandon S. ; Wong, Fay ; Azad, Nilofer S. ; Rucki, Agnieszka A. ; Laheru, Dan ; Donehower, Ross ; 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, Ludmila ; Cope, Leslie ; Meyer, Christian ; Zhou, Shibin ; Goldberg, Richard M. ; Armstrong, Deborah K. ; Bever, Katherine M. ; Fader, Amanda N. ; Taube, Janis ; Housseau, Franck ; Spetzler, David ; Xiao, Nianqing ; Pardoll, Drew M. ; Papadopoulos, Nickolas ; Kinzler, Kenneth W. ; Eshleman, James R. ; 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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AU - Aulakh,Laveet K.

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AU - Luber,Brandon S.

AU - Wong,Fay

AU - Azad,Nilofer S.

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AU - Donehower,Ross

AU - Zaheer,Atif

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AU - Lee,James J.

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AU - Joe,Andrew

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AU - Holdhoff,Matthias

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AU - Cope,Leslie

AU - Meyer,Christian

AU - Zhou,Shibin

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AU - Armstrong,Deborah K.

AU - Bever,Katherine M.

AU - Fader,Amanda N.

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AU - Xiao,Nianqing

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AU - Papadopoulos,Nickolas

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AU - Vogelstein,Bert

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AU - Diaz,Luis A.

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