• A Corrigendum to this article was published on 14 March 2018

This article has been updated


Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens1, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response2, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.

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Change history

  • 14 March 2018

    Please see accompanying Corrigendum (http://doi.org/10.1038/nature25145). The ‘Data availability’ statement was changed from ‘All data are available from the corresponding author upon reasonable request’ to ‘WES and RNA-seq data are deposited in dbGaP (https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001451.v1.p1). All other data are available from the corresponding author upon reasonable request’ In addition, the following wording was added to the ‘Competing interests’ statement: ‘C.J.W. is subject to a conflict of interest management plan for the reported studies because of her competing financial interests in Neon Therapeutics. Under this plan, C.J.W. may not access identifiable human subjects’ data nor otherwise participate directly in the IRB-approved protocol reported herein. C.J.W.’s contributions to the overall program strategy and data analyses occurred on a de-identified basis.’


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We thank J. Russell and the Dana-Farber Cancer Institute (DFCI) Center for Immuno-Oncology (CIO) staff; M. Copersino (Regulatory Affairs), B. Meyers, C. Harvey, and S. Bartel (Clinical Pharmacy); A. Lako (CIO), M. Bowden (Center for Molecular Oncologic Pathology); O. Sturtevant, H. Negre, S. Y. Kim, M. A. Kelley (Cell Manipulation Core Facility) and the Pasquarello Tissue Bank (all at DFCI); T. Bowman (DFHCC Specialized Histopathology Core Laboratory); the Broad Institute’s Biological Samples, Genetic Analysis, and Genome Sequencing Platforms; S. Hodi, G. Dranoff, M. Rajasagi, U. Burkhardt, S. Sarkizova, J. Fan, and P. Bachireddy for discussions; J. Petricciani and M. Krane for regulatory advice; B. McDonough (CSBio) and S. Thorne (CuriRx) for peptide development. This research was made possible by a gift from the Blavatnik Family Foundation, and was supported by grants from the Broad Institute SPARC program and the National Institutes of Health (NCI-1RO1CA155010-02 (to C.J.W.), NHLBI-5R01HL103532-03 (to C.J.W.), NCI-SPORE-2P50CA101942-11A1 (to D.B.K.); NCI-R50 RCA211482A (to S.S.)), from the Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund (to P.A.O.), the Faircloth Family Research Fund (to P.A.O.), and the DFCI Center for Cancer Immunotherapy Research fellowship (to Z.H.). C.J.W. is a scholar of the Leukemia and Lymphoma Society.

Author information

Author notes

    • Edward F. Fritsch

    Present address: Neon Therapeutics, Inc. Cambridge, Massachusetts 02139, USA.

    • Patrick A. Ott
    •  & Zhuting Hu

    These authors contributed equally to this work.


  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Patrick A. Ott
    • , Zhuting Hu
    • , Derin B. Keskin
    • , Sachet A. Shukla
    • , Jing Sun
    • , David J. Bozym
    • , Wandi Zhang
    • , Christina Chen
    • , Oriol Olive
    • , Heather Daley
    • , Elizabeth I. Buchbinder
    • , Gad Getz
    • , Jerome Ritz
    • , Edward F. Fritsch
    • , Nir Hacohen
    •  & Catherine J. Wu
  2. Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA

    • Patrick A. Ott
    • , Elizabeth I. Buchbinder
    • , Jerome Ritz
    •  & Catherine J. Wu
  3. Harvard Medical School, Boston, Massachusetts 02215, USA

    • Patrick A. Ott
    • , Derin B. Keskin
    • , Elizabeth I. Buchbinder
    • , Charles H. Yoon
    • , Dan H. Barouch
    • , Jon C. Aster
    • , Gad Getz
    • , Kai Wucherpfennig
    • , Jerome Ritz
    • , Eric S. Lander
    • , Nir Hacohen
    •  & Catherine J. Wu
  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Derin B. Keskin
    • , Sachet A. Shukla
    • , Todd A. Carter
    • , Shuqiang Li
    • , David J. Lieb
    • , Thomas Eisenhaure
    • , Maegan Harden
    • , Niall Lennon
    • , Stacey Gabriel
    • , Gad Getz
    • , Eric S. Lander
    • , Edward F. Fritsch
    • , Nir Hacohen
    •  & Catherine J. Wu
  5. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Adrienne Luoma
    •  & Kai Wucherpfennig
  6. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Anita Giobbie-Hurder
    •  & Donna Neuberg
  7. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA

    • Lauren Peter
    • , Michael Seaman
    •  & Dan H. Barouch
  8. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA

    • Lauren Peter
    •  & Dan H. Barouch
  9. Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Evisa Gjini
    •  & Scott J. Rodig
  10. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA

    • Jonathan Stevens
    • , William J. Lane
    • , Scott J. Rodig
    •  & Jon C. Aster
  11. CuriRx, Inc., Wilmington, Massachusetts 01887, USA

    • Indu Javeri
    •  & Kaliappanadar Nellaiappan
  12. Oncovir, Inc., 3203 Cleveland Avenue, NW, Washington DC 20008, USA

    • Andres M. Salazar
  13. Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA

    • Charles H. Yoon
  14. Department of Pathology, Massachusetts General Hospital, Boston Massachusetts 02214, USA

  15. Center for Cancer Research, Massachusetts General Hospital, Boston Massachusetts 02214, USA


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P.A.O. was the principal investigator and Investigational New Drug holder. C.J.W., N.H., P.A.O., and E.F.F. directed the overall study design. Z.H. designed and performed experimental and data analysis with D.B.K., D.J.B., W.Z., L.P., C.C., S.L., and D.J.L.; S.A.S., T.A.C., J.S., J.S., W.J.L., and E.F.F. analysed sequencing data and selected neoantigen targets; D.H.B. and M.S. enabled sample collection and immune monitoring; H.D. and J.R. directed vaccine preparation; A.L. and K.W. designed and generated tetramers; A.G.H. and D.N. designed and performed statistical analyses; T.E., A.M.S., I.J., and K.N. helped design the vaccine formulation; O.O. coordinated clinical research; P.A.O., E.I.B., and C.H.Y. provided patient samples; J.C.A., E.G., and S.J.R performed pathology review; M.H., N.L., S.G., and G.G. helped devise the computational pipeline; N.H., C.J.W., E.F.F., T.A.C., and E.S.L. developed the overall program strategy. P.A.O., Z.H., E.F.F., N.H., and C.J.W. wrote the manuscript; all authors discussed and interpreted results.

Competing interests

E.F.F. is a founder and employee of Neon Therapeutics. N.H. and C.J.W. are founders of Neon Therapeutics and members of its scientific advisory board. P.A.O. has advised Neon Therapeutics. E.S.L. is a founder of Neon Therapeutics and a member of its board of directors. K.N. and I.J. are employees of CuriRx. Patent applications have been filed on aspects of the described work entitled as follows: Compositions and Methods for Personalized Neoplasia Vaccines (N.H., E.F.F., and C.J.W.), Methods for Identifying Tumour Specific Neo-Antigens (N.H. and C.J.W.), Formulations for Neoplasia Vaccines (E.F.F., K.N., and I.J.), and Combination Therapy for Neoantigen Vaccine (N.H., C.J.W., and E.F.F.). S.J.R. receives research funding from Bristol-Myers Squibb, MedImmune, and is on the scientific advisory board for Perkin Elmer. The remaining authors declare no competing financial interests. A.M.S. is a founder and employee of Oncovir, Inc. C.J.W. is subject to a conflict of interest management plan for the reported studies because of her competing financial interests in Neon Therapeutics. Under this plan, C.J.W. may not access identifiable human subjects’ data nor otherwise participate directly in the IRB-approved protocol reported herein. C.J.W.’s contributions to the overall program strategy and data analyses occurred on a de-identified basis.

Corresponding author

Correspondence to Catherine J. Wu.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table contains QC metrics of whole-exome sequencing and RNA-sequencing for Patients 1-10. Sheet a contains whole exome sequencing. Sheet b contains RNA sequencing.

  2. 2.

    Supplementary Table 2

    This table contains somatic mutations identified from Patients 1-10.

  3. 3.

    Supplementary Table 3

    This table contains a summary of the number of identified somatic mutations, predicted HLA binders and synthesized immunizing peptides for Patients 1-10.

  4. 4.

    Supplementary Table 4

    This table contains patient information. Sheet a contains HLA allotypes of all subjects. Sheet b contains treatment-related adverse events.

  5. 5.

    Supplementary Table 5

    This table contains a summary of expression and class I prediction related to the immunizing peptides for Patients 1-6.

  6. 6.

    Supplementary Table 6

    This table a summary of class II prediction related to the immunizing peptides for Patients 1-6.

  7. 7.

    Supplementary Table 7

    This table contains differential analysis of single cell gene expression of CD4+ T cells pre-vaccination and tetramer-positive CD4+ T cells post-vaccination for Patients 1 and 4. Sheet a contains Patient 1, sheet b contains Patient 4, sheet c contains Patient 1 and 4 and sheet d Patient 1 and 4 intersection.

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