analyzed above, the frequencies of these functionally validated MANA-specific T cell clones peaked
soon after treatment and corresponded with nor-malization of the systemic tumor marker, predating objective radiographic response by several
weeks. This peak in T cell clonal expansion was
followed by decreases in frequency, reminiscent
of T cell responses to acute viral infections (Fig.
2E). Because all the MANAs were from frameshift mutations, only MANA2 had a similar wild-type counterpart (differing in the two C-terminal
amino acids). The corresponding wild-type peptide bound to HLA with less than 1% of the affinity of the mutant peptide counterpart (Fig. 2F),
consistent with the mutation conferring enhanced
To estimate the proportion of cancer patients
for whom the results of this study might be applicable, we evaluated 12,019 cancers representing 32 distinct tumor types for mismatch repair
deficiency using a next-generation sequencing–
based approach (Fig. 3). In accordance with a
recent independent estimate using a different
approach (23), we found that >2% of adenocarcinomas of the endometrium, stomach, small intestine, colon and rectum, cervix, prostate, bile
duct, and liver, as well as neuroendocrine tumors, uterine sarcomas, and thyroid carcinomas,
were mismatch repair–deficient. Across these
11 tumor types, 10% of stage I to stage III cancers
and 5% of stage IV cancers were mismatch repair–
deficient. This represents roughly 40,000 annual
stage I to III diagnoses and 20,000 stage IV diagnoses in the United States alone. Because genetic
and immunohistochemical tests for mismatch
repair deficiency are already widely available,
these results tie immunity, cancer genetics, and
therapeutics together in a manner that will likely
establish a new standard of care. In the future,
testing for mismatch repair deficiency in patients
who are refractory to other treatments might be
considered in order to identify those who may
benefit from PD-1 pathway blockade, regardless of tumor type.
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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.
Materials and Methods
Figs. S1 to S4
Tables S1 to S10
17 May 2017; accepted 1 June 2017
Published online 8 June 2017
Fig. 3. Mismatch repair
12,019 tumors. The proportion of mismatch
in each cancer subtype is
expressed as a percentage. Mismatch repair–
deficient tumors were
identified in 24 of 32
tumor subtypes tested,
more often in early-stage
disease (defined as
stage < IV).