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 language | English (US) |
|---|---|
| Pages (from-to) | 409-413 |
| Number of pages | 5 |
| Journal | Science |
| Volume | 357 |
| Issue number | 6349 |
| DOIs | |
| State | Published - Jul 28 2017 |
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ASJC Scopus subject areas
- Medicine(all)
- General
Cite this
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: Contribution to journal › Article
}
TY - JOUR
T1 - Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
AU - Le,Dung T.
AU - Durham,Jennifer N.
AU - Smith,Kellie N.
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 S.
AU - Rucki,Agnieszka A.
AU - Laheru,Dan
AU - Donehower,Ross
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,Ludmila
AU - Cope,Leslie
AU - Meyer,Christian
AU - Zhou,Shibin
AU - Goldberg,Richard M.
AU - Armstrong,Deborah K.
AU - Bever,Katherine M.
AU - Fader,Amanda N.
AU - Taube,Janis
AU - Housseau,Franck
AU - Spetzler,David
AU - Xiao,Nianqing
AU - Pardoll,Drew M.
AU - Papadopoulos,Nickolas
AU - Kinzler,Kenneth W.
AU - Eshleman,James R.
AU - Vogelstein,Bert
AU - Anders,Robert A.
AU - Diaz,Luis A.
PY - 2017/7/28
Y1 - 2017/7/28
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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U2 - 10.1126/science.aan6733
DO - 10.1126/science.aan6733
M3 - Article
VL - 357
SP - 409
EP - 413
JO - Science
T2 - Science
JF - Science
SN - 0036-8075
IS - 6349
ER -