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

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Science  28 Jul 2017:
Vol. 357, Issue 6349, pp. 409-413
DOI: 10.1126/science.aan6733
  • Fig. 1 Patient survival and clinical response to pembrolizumab across 12 different tumor types with mismatch repair deficiency.

    (A) Tumor types across 86 patients. (B) Waterfall plot of all radiographic responses across 12 different tumor types at 20 weeks. Tumor responses were measured at regular intervals; values show the best fractional change of the sum of longest diameters (SLD) from the baseline measurements of each measurable tumor. (C) Confirmed radiographic objective responses at 20 weeks (blue) compared to the best radiographic responses in the same patients (red). The mean time to the best radiographic response was 28 weeks. (D) Swimmer plot showing survival for each patient with mismatch repair–deficient tumors, indicating death, progression, and time off therapy. (E and F) Kaplan-Meier estimates of progression-free survival (E) and overall patient survival (F).

  • Fig. 2 TCR clonal dynamics and mutation­-associated neoantigen recognition in patients responding to PD-1 blockade.

    (A) TCR sequencing was performed on serial peripheral T cell samples obtained before and after PD-1 blockade. Tumor tissue with mismatch repair deficiency was obtained from three responding patients. Shown for each patient are 15 TCR clones with the highest relative change in frequency after treatment (left) that were also found in the original tumor (right panels). (B) Whole-exome sequencing was performed on tumor and matched normal tissue from patient 19. Somatic alterations were analyzed using a neoantigen prediction pipeline to identify putative MANAs. Reactivity to 15 candidate MANAs was tested in a 10-day cultured IFN-γ ELISpot assay. Data are shown as the mean number of spot-forming cells (SFC) per 106 T cells (left) or mean cytokine activity (right) of triplicate wells ± SD. *P < 0.05, **P < 0.01, ***P < 0.001. (C) Seven candidate MANAs were selected for TCR analysis on the basis of ELISpot reactivity. (D) MANA-specific T cell responses were identified against three of seven candidate MANAs (MANA1, MANA2, and MANA4) after 10 days of in vitro stimulation (left panels). MANA-specific clones were identified by significant expansion in response to the relevant peptide and no significant expansion in response to any other peptide tested (fig. S3). Data are shown as the relative change in TCR clone frequency compared to the frequency of that clone after identical culture without peptide. These T cell clones were also found in the original tumor biopsy (right panels). (E) Frequency of MANA-specific clones, carcinoembryonic antigen (CEA), and radiographic response in the tumor [from (D)] were tracked in the peripheral blood before treatment and at various times after pembrolizumab treatment. Time is shown in weeks after the first pembrolizumab dose. (F) In vitro binding and stability assays demonstrate the affinity kinetics of each relevant MANA and the corresponding wild-type peptide (when applicable) for their restricting HLA class I allele. The A*02:01-restricted influenza M GILGFVTL epitope was used as a negative control for each assay; known HLA-matched epitopes were used as positive controls when available. Data are shown as counts per second with increasing peptide concentration for binding assays (top) or counts per minute over time for stability assays (bottom). Data points indicate the mean of two independent experiments ± SD. Amino acid abbreviations: A, Ala; C, Cys; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L, Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; W, Trp; Y, Tyr.

  • Fig. 3 Mismatch repair deficiency across 12,019 tumors.

    The proportion of mismatch repair–deficient tumors 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).

  • Table 1 Summary of therapeutic response to pembrolizumab (anti–PD-1) treatment.

    Radiographic responses, progression-free survival (PFS), and overall survival (OS) estimates were measured using RECIST v1.1 guidelines. Patients were considered not evaluable if clinical progression precluded a 12-week scan. The rate of disease control was defined as the percentage of patients who had a complete response, partial response, or stable disease for 12 weeks or more. NR, not reached.

    Type of responsePatients (n = 86)
    Complete response18 (21%)
    Partial response28 (33%)
    Stable disease20 (23%)
    Progressive disease12 (14%)
    Not evaluable8 (9%)
    Objective response rate53%
    95% CI42 to 64%
    Disease control rate77%
    95% CI66 to 85%
    Median progression-free survival timeNR
    95% CI14.8 months to NR
    2-year progression-free survival rate53%
    95% CI42 to 68%
    Median overall survival timeNR
    95% CINR to NR
    2-year overall survival rate64%
    95% CI53 to 78%

Supplementary Materials

  • 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, 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 Jr.

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Materials and Methods
    • Figs. S1 to S4
    • Tables S1 to S7
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    Tables S8 to S10

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