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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
DOI: 10.1126/science.aan6733
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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 (24–36)

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References and Notes

1
S. L. Topalian, C. G. Drake, D. M. Pardoll, Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
2
P. C. Tumeh, C. L. Harview, J. H. Yearley, I. P. Shintaku, E. J. Taylor, L. Robert, B. Chmielowski, M. Spasic, G. Henry, V. Ciobanu, A. N. West, M. Carmona, C. Kivork, E. Seja, G. Cherry, A. J. Gutierrez, T. R. Grogan, C. Mateus, G. Tomasic, J. A. Glaspy, R. O. Emerson, H. Robins, R. H. Pierce, D. A. Elashoff, C. Robert, A. Ribas, PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
3
D. F. McDermott, C. G. Drake, M. Sznol, T. K. Choueiri, J. D. Powderly, D. C. Smith, J. R. Brahmer, R. D. Carvajal, H. J. Hammers, I. Puzanov, F. S. Hodi, H. M. Kluger, S. L. Topalian, D. M. Pardoll, J. M. Wigginton, G. D. Kollia, A. Gupta, D. McDonald, V. Sankar, J. A. Sosman, M. B. Atkins, Survival, durable response, and long-term safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J. Clin. Oncol. 33, 2013–2020 (2015).
4
S. L. Topalian, M. Sznol, D. F. McDermott, H. M. Kluger, R. D. Carvajal, W. H. Sharfman, J. R. Brahmer, D. P. Lawrence, M. B. Atkins, J. D. Powderly, P. D. Leming, E. J. Lipson, I. Puzanov, D. C. Smith, J. M. Taube, J. M. Wigginton, G. D. Kollia, A. Gupta, D. M. Pardoll, J. A. Sosman, F. S. Hodi, Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).
5
S. N. Gettinger, L. Horn, L. Gandhi, D. R. Spigel, S. J. Antonia, N. A. Rizvi, J. D. Powderly, R. S. Heist, R. D. Carvajal, D. M. Jackman, L. V. Sequist, D. C. Smith, P. Leming, D. P. Carbone, M. C. Pinder-Schenck, S. L. Topalian, F. S. Hodi, J. A. Sosman, M. Sznol, D. F. McDermott, D. M. Pardoll, V. Sankar, C. M. Ahlers, M. Salvati, J. M. Wigginton, M. D. Hellmann, G. D. Kollia, A. K. Gupta, J. R. Brahmer, Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).
6
J. M. Taube, A. Klein, J. R. Brahmer, H. Xu, X. Pan, J. H. Kim, L. Chen, D. M. Pardoll, S. L. Topalian, R. A. Anders, Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).
7
N. J. Llosa, M. Cruise, A. Tam, E. C. Wicks, E. M. Hechenbleikner, J. M. Taube, R. L. Blosser, H. Fan, H. Wang, B. S. Luber, M. Zhang, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, C. L. Sears, R. A. Anders, D. M. Pardoll, F. Housseau, The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).
8
R. S. Herbst, J. C. Soria, M. Kowanetz, G. D. Fine, O. Hamid, M. S. Gordon, J. A. Sosman, D. F. McDermott, J. D. Powderly, S. N. Gettinger, H. E. Kohrt, L. Horn, D. P. Lawrence, S. Rost, M. Leabman, Y. Xiao, A. Mokatrin, H. Koeppen, P. S. Hegde, I. Mellman, D. S. Chen, F. S. Hodi, Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
9
N. A. Rizvi, M. D. Hellmann, A. Snyder, P. Kvistborg, V. Makarov, J. J. Havel, W. Lee, J. Yuan, P. Wong, T. S. Ho, M. L. Miller, N. Rekhtman, A. L. Moreira, F. Ibrahim, C. Bruggeman, B. Gasmi, R. Zappasodi, Y. Maeda, C. Sander, E. B. Garon, T. Merghoub, J. D. Wolchok, T. N. Schumacher, T. A. Chan, Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015).
10
W. Hugo, J. M. Zaretsky, L. Sun, C. Song, B. H. Moreno, S. Hu-Lieskovan, B. Berent-Maoz, J. Pang, B. Chmielowski, G. Cherry, E. Seja, S. Lomeli, X. Kong, M. C. Kelley, J. A. Sosman, D. B. Johnson, A. Ribas, R. S. Lo, Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 168, 542 (2017).
11
N. H. Segal, D. W. Parsons, K. S. Peggs, V. Velculescu, K. W. Kinzler, B. Vogelstein, J. P. Allison, Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008).
12
M. M. Gubin, X. Zhang, H. Schuster, E. Caron, J. P. Ward, T. Noguchi, Y. Ivanova, J. Hundal, C. D. Arthur, W. J. Krebber, G. E. Mulder, M. Toebes, M. D. Vesely, S. S. Lam, A. J. Korman, J. P. Allison, G. J. Freeman, A. H. Sharpe, E. L. Pearce, T. N. Schumacher, R. Aebersold, H. G. Rammensee, C. J. Melief, E. R. Mardis, W. E. Gillanders, M. N. Artyomov, R. D. Schreiber, Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
13
T. N. Schumacher, R. D. Schreiber, Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
14
J. P. Ward, M. M. Gubin, R. D. Schreiber, The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv. Immunol. 130, 25–74 (2016).
15
C. Lengauer, K. W. Kinzler, B. Vogelstein, Genetic instabilities in human cancers. Nature 396, 643–649 (1998).
16
H. Kim, J. Jen, B. Vogelstein, S. R. Hamilton, Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 145, 148–156 (1994).
17
T. C. Smyrk, P. Watson, K. Kaul, H. T. Lynch, Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma. Cancer 91, 2417–2422 (2001).
18
R. Dolcetti, A. Viel, C. Doglioni, A. Russo, M. Guidoboni, E. Capozzi, N. Vecchiato, E. Macrì, M. Fornasarig, M. Boiocchi, High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am. J. Pathol. 154, 1805–1813 (1999).
19
D. T. Le, J. N. Uram, H. Wang, B. R. Bartlett, H. Kemberling, A. D. Eyring, A. D. Skora, B. S. Luber, N. S. Azad, D. Laheru, B. Biedrzycki, R. C. Donehower, A. Zaheer, G. A. Fisher, T. S. Crocenzi, J. J. Lee, S. M. Duffy, R. M. Goldberg, A. de la Chapelle, M. Koshiji, F. Bhaijee, T. Huebner, R. H. Hruban, L. D. Wood, N. Cuka, D. M. Pardoll, N. Papadopoulos, K. W. Kinzler, S. Zhou, T. C. Cornish, J. M. Taube, R. A. Anders, J. R. Eshleman, B. Vogelstein, L. A. Diaz Jr., PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
20
M. Overman, S. Lonardi, F. Leone, R. S. McDermott, M. A. Morse, K. Y. M. Wong, B. Neyns, J. L. Leach, P. Garcia Alfonso, J. J. Lee, A. Hill, H.-J. Lenz, J. Desai, R. A. Moss, Z. A. Cao, J.-M. Ledeine, H. Tang, S. Kopetz, T. Andre, Nivolumab in patients with DNA mismatch repair deficient/microsatellite instability high metastatic colorectal cancer: Update from CheckMate 142. J. Clin. Oncol. 35 (suppl.), 519 (2017).
21
A. Grothey, E. Van Cutsem, A. Sobrero, S. Siena, A. Falcone, M. Ychou, Y. Humblet, O. Bouché, L. Mineur, C. Barone, A. Adenis, J. Tabernero, T. Yoshino, H. J. Lenz, R. M. Goldberg, D. J. Sargent, F. Cihon, L. Cupit, A. Wagner, D. Laurent, Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).
22
J. M. Zaretsky, A. Garcia-Diaz, D. S. Shin, H. Escuin-Ordinas, W. Hugo, S. Hu-Lieskovan, D. Y. Torrejon, G. Abril-Rodriguez, S. Sandoval, L. Barthly, J. Saco, B. Homet Moreno, R. Mezzadra, B. Chmielowski, K. Ruchalski, I. P. Shintaku, P. J. Sanchez, C. Puig-Saus, G. Cherry, E. Seja, X. Kong, J. Pang, B. Berent-Maoz, B. Comin-Anduix, T. G. Graeber, P. C. Tumeh, T. N. Schumacher, R. S. Lo, A. Ribas, Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
23
R. J. Hause, C. C. Pritchard, J. Shendure, S. J. Salipante, Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016).
24
V. Anagnostou, K. N. Smith, P. M. Forde, N. Niknafs, R. Bhattacharya, J. White, T. Zhang, V. Adleff, J. Phallen, N. Wali, C. Hruban, V. B. Guthrie, K. Rodgers, J. Naidoo, H. Kang, W. Sharfman, C. Georgiades, F. Verde, P. Illei, Q. K. Li, E. Gabrielson, M. V. Brock, C. A. Zahnow, S. B. Baylin, R. B. Scharpf, J. R. Brahmer, R. Karchin, D. M. Pardoll, V. E. Velculescu, Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 7, 264–276 (2017).
25
C. S. Carlson, R. O. Emerson, A. M. Sherwood, C. Desmarais, M. W. Chung, J. M. Parsons, M. S. Steen, M. A. LaMadrid-Herrmannsfeldt, D. W. Williamson, R. J. Livingston, D. Wu, B. L. Wood, M. J. Rieder, H. Robins, Using synthetic templates to design an unbiased multiplex PCR assay. Nat. Commun. 4, 2680 (2013).
26
H. S. Robins, P. V. Campregher, S. K. Srivastava, A. Wacher, C. J. Turtle, O. Kahsai, S. R. Riddell, E. H. Warren, C. S. Carlson, Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells. Blood 114, 4099–4107 (2009).
27
J. W. Bacher, L. A. Flanagan, R. L. Smalley, N. A. Nassif, L. J. Burgart, R. B. Halberg, W. M. Megid, S. N. Thibodeau, Development of a fluorescent multiplex assay for detection of MSI-high tumors. Dis. Markers 20, 237–250 (2004).
28
K. M. Murphy, S. Zhang, T. Geiger, M. J. Hafez, J. Bacher, K. D. Berg, J. R. Eshleman, Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J. Mol. Diagn. 8, 305–311 (2006).
29
J. D. Wolchok, A. Hoos, S. O’Day, J. S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, O. Bohnsack, G. Nichol, R. Humphrey, F. S. Hodi, Guidelines for the evaluation of immune therapy activity in solid tumors: Immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).
30
N. J. Llosa, M. Cruise, A. Tam, E. C. Wicks, E. M. Hechenbleikner, J. M. Taube, R. L. Blosser, H. Fan, H. Wang, B. S. Luber, M. Zhang, N. Papadopoulos, K. W. Kinzler, B. Vogelstein, C. L. Sears, R. A. Anders, D. M. Pardoll, F. Housseau, The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).
31
J. M. Taube, R. A. Anders, G. D. Young, H. Xu, R. Sharma, T. L. McMiller, S. Chen, A. P. Klein, D. M. Pardoll, S. L. Topalian, L. Chen, Colocalization of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl. Med. 4, 127ra37 (2012).
32
N. Cuka, H. Hempel, K. Sfanos, A. De Marzo, T. Cornish, PIP: An open source framework for multithreaded image analysis of whole slide images. Lab. Invest. 94, 398A (2014).
33
J. Cupitt, K. Martinez, in Electronic Imaging: Science & Technology (International Society for Optics and Photonics, 1996), pp. 19–28.
34
S. Jones, V. Anagnostou, K. Lytle, S. Parpart-Li, M. Nesselbush, D. R. Riley, M. Shukla, B. Chesnick, M. Kadan, E. Papp, K. G. Galens, D. Murphy, T. Zhang, L. Kann, M. Sausen, S. V. Angiuoli, L. A. Diaz Jr., V. E. Velculescu, Personalized genomic analyses for cancer mutation discovery and interpretation. Sci. Transl. Med. 7, 283ra53 (2015).
35
M. Sausen, R. J. Leary, S. Jones, J. Wu, C. P. Reynolds, X. Liu, A. Blackford, G. Parmigiani, L. A. Diaz Jr., N. Papadopoulos, B. Vogelstein, K. W. Kinzler, V. E. Velculescu, M. D. Hogarty, Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat. Genet. 45, 12–17 (2013).
36
S. B. Needleman, C. D. Wunsch, A general method applicable to the search for similarities in the amino acid sequence of two proteins. J. Mol. Biol. 48, 443–453 (1970).

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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

Dung T. Le https://orcid.org/0000-0002-2110-7697
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.
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Jennifer N. Durham* https://orcid.org/0000-0001-9097-9125
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.
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Kellie N. Smith* https://orcid.org/0000-0002-6295-8930
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.
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Hao Wang*
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Bjarne R. Bartlett* https://orcid.org/0000-0001-8579-0379
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.
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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.
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Steve Lu https://orcid.org/0000-0002-8201-8583
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.
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Holly Kemberling https://orcid.org/0000-0002-2997-324X
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Cara Wilt https://orcid.org/0000-0002-4054-7452
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Brandon S. Luber
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Fay Wong https://orcid.org/0000-0001-9759-3778
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.
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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.
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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.
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Dan Laheru
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Ross Donehower
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Atif Zaheer https://orcid.org/0000-0002-4824-6654
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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George A. Fisher
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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Todd S. Crocenzi https://orcid.org/0000-0001-8762-1990
Providence Cancer Center at Providence Health & Services, Portland, OR 97213, USA.
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James J. Lee https://orcid.org/0000-0001-6749-9350
Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
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Tim F. Greten https://orcid.org/0000-0002-0806-2535
Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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Austin G. Duffy https://orcid.org/0000-0001-9277-0157
Gastrointestinal Malignancies Section, Thoracic-GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
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Kristen K. Ciombor https://orcid.org/0000-0002-8992-9515
Division of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
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Aleksandra D. Eyring
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
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Bao H. Lam
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
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Andrew Joe
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
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S. Peter Kang
Merck & Co. Inc., Kenilworth, NJ 07033, USA.
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Matthias Holdhoff
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Ludmila Danilova https://orcid.org/0000-0003-2813-3094
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.
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Leslie Cope https://orcid.org/0000-0002-4098-3289
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.
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Christian Meyer https://orcid.org/0000-0003-3329-7106
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Shibin Zhou https://orcid.org/0000-0003-1941-4425
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.
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Richard M. Goldberg https://orcid.org/0000-0003-0308-8223
West Virginia University Cancer Institute, Morgantown, WV 26506, USA.
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Deborah K. Armstrong
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Katherine M. Bever https://orcid.org/0000-0001-5230-4661
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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Amanda N. Fader
Department of Gynecology and Obstetrics, Johns Hopkins Medicine, Baltimore, MD 21287, USA.
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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.
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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.
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David Spetzler
Caris Life Sciences, Phoenix, AZ 85040, USA.
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Nianqing Xiao https://orcid.org/0000-0001-9388-5028
Caris Life Sciences, Phoenix, AZ 85040, USA.
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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.
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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.
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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.
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James R. Eshleman https://orcid.org/0000-0002-9274-8459
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Bert Vogelstein https://orcid.org/0000-0003-0766-3854
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.
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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.
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Luis A. Diaz Jr.‡ https://orcid.org/0000-0002-7079-8914 [email protected]
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.
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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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    • H. Brittain,
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