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

Dung T. Le https://orcid.org/0000-0002-2110-7697, Jennifer N. Durham https://orcid.org/0000-0001-9097-9125, Kellie N. Smith https://orcid.org/0000-0002-6295-8930, Hao Wang, Bjarne R. Bartlett https://orcid.org/0000-0001-8579-0379, Laveet K. Aulakh, Steve Lu https://orcid.org/0000-0002-8201-8583, Holly Kemberling https://orcid.org/0000-0002-2997-324X, Cara Wilt https://orcid.org/0000-0002-4054-7452, Brandon S. Luber, Fay Wong https://orcid.org/0000-0001-9759-3778, Nilofer S. Azad, Agnieszka A. Rucki, Dan Laheru, Ross Donehower, Atif Zaheer https://orcid.org/0000-0002-4824-6654, George A. Fisher, Todd S. Crocenzi https://orcid.org/0000-0001-8762-1990, James J. Lee https://orcid.org/0000-0001-6749-9350, Tim F. Greten https://orcid.org/0000-0002-0806-2535, Austin G. Duffy https://orcid.org/0000-0001-9277-0157, Kristen K. Ciombor https://orcid.org/0000-0002-8992-9515, Aleksandra D. Eyring, Bao H. Lam, Andrew Joe, S. Peter Kang, Matthias Holdhoff, Ludmila Danilova https://orcid.org/0000-0003-2813-3094, Leslie Cope https://orcid.org/0000-0002-4098-3289, Christian Meyer https://orcid.org/0000-0003-3329-7106, Shibin Zhou https://orcid.org/0000-0003-1941-4425, Richard M. Goldberg https://orcid.org/0000-0003-0308-8223, Deborah K. Armstrong, Katherine M. Bever https://orcid.org/0000-0001-5230-4661, Amanda N. Fader, Janis Taube, Franck Housseau, David Spetzler, Nianqing Xiao https://orcid.org/0000-0001-9388-5028, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, James R. Eshleman https://orcid.org/0000-0002-9274-8459, Bert Vogelstein https://orcid.org/0000-0003-0766-3854, Robert A. Anders, and Luis A. Diaz Jr. https://orcid.org/0000-0002-7079-8914 [email protected]Authors Info & Affiliations
Science
8 Jun 2017
Vol 357, Issue 6349
pp. 409-413

Predicting responses to immunotherapy

Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers.
Science, this issue p. 409; see also p. 358

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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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S4
Tables S1 to S10
References (2436)

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Science
Volume 357 | Issue 6349
28 July 2017

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Received: 17 May 2017
Accepted: 1 June 2017
Published in print: 28 July 2017

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Acknowledgments

The data reported are tabulated in the main text and supplementary materials. The raw TCR RNA sequence data have been deposited into the ImmuneACCESS project repository of the Adaptive Biotech database, under the following link: https://clients.adaptivebiotech.com/pub/diaz-2017-science. We thank K. Helwig for administrative support, C. Blair for outstanding technical assistance, and E. H. Rubin, R. Dansey, and R. Perlmutter at Merck & Co. Inc. (Kenilworth, NJ) for supporting this research. Funded by the Swim Across America Laboratory at Johns Hopkins, the Ludwig Center for Cancer Genetics and Therapeutics, the Howard Hughes Medical Institutes, the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the 2017 Stand Up to Cancer Colon Cancer Dream Team, the Commonwealth Fund, the Banyan Gate Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Bloomberg Foundation, the Sol Goldman Pancreatic Cancer Research Center, Merck & Co. Inc., Gastrointestinal SPORE grant P50CA062924, and NIH grants P30CA006973, CA163672, CA43460, CA203891, CA67941, CA16058, and CA57345. L.D., D.L., B.V., N.P., and K.W.K. are inventors on a patent application (PCT/US2015/060331 or WO 2016077553 A1) submitted by Johns Hopkins University that covers checkpoint blockade and microsatellite instability. L.D., B.V., N.P., and K.W.K. are founders of PapGene and Personal Genome Diagnostics (PGDx). L.D. is a consultant for Merck, Illumina, PGDx, and Cell Design Labs. PGDx and PapGene, as well as other companies, have licensed technologies from Johns Hopkins University, on which L.D., B.V., N.P., and K.W.K. are inventors. Some of these licenses and relationships are associated with equity or royalty payments. The terms of these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with its conflict-of-interest policies.

Authors

Affiliations

Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Hao Wang*
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Laveet K. Aulakh
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Brandon S. Luber
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Nilofer S. Azad
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Agnieszka A. Rucki
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Dan Laheru
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ross Donehower
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
George A. Fisher
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Providence Cancer Center at Providence Health & Services, Portland, OR 97213, USA.
Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Aleksandra D. Eyring
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
Bao H. Lam
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
Andrew Joe
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
S. Peter Kang
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
Matthias Holdhoff
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
West Virginia University Cancer Institute, Morgantown, WV 26506, USA.
Deborah K. Armstrong
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Amanda N. Fader
Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD 21287, USA.
Janis Taube
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Franck Housseau
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
David Spetzler
Caris Life Sciences, Phoenix, AZ 85040, USA.
Caris Life Sciences, Phoenix, AZ 85040, USA.
Drew M. Pardoll
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Nickolas Papadopoulos
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Kenneth W. Kinzler
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, MD 21287, USA.
Robert A. Anders
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA.
Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21287, USA.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
Present address: Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Funding Information

Commonwealth Fund: award315544
Stand Up To Cancer: award315548
Bloomberg Kimmel Institute for Cancer Immunotherapy: award315542
Swim Across America: award315543
The Banyan Gate Foundation: award315546

Notes

*
These authors contributed equally to this work.
Corresponding author. Email: [email protected]

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