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Nature. 2017 Jul 13;547(7662):217-221. doi: 10.1038/nature22991. Epub 2017 Jul 5.

An immunogenic personal neoantigen vaccine for patients with melanoma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
2
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
3
Harvard Medical School, Boston, Massachusetts 02215, USA.
4
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
5
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
6
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
7
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
8
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA.
9
Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
10
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
11
CuriRx, Inc., Wilmington, Massachusetts 01887, USA.
12
Oncovir, Inc., 3203 Cleveland Avenue, NW, Washington DC 20008, USA.
13
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.

Abstract

Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, 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 response, 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.

PMID:
28678778
PMCID:
PMC5577644
DOI:
10.1038/nature22991
[Indexed for MEDLINE]
Free PMC Article

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