PMID- 28678778
OWN - NLM
STAT- MEDLINE
DCOM- 20171205
LR  - 20220321
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 547
IP  - 7662
DP  - 2017 Jul 13
TI  - An immunogenic personal neoantigen vaccine for patients with melanoma.
PG  - 217-221
LID - 10.1038/nature22991 [doi]
AB  - 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.
FAU - Ott, Patrick A
AU  - Ott PA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
FAU - Hu, Zhuting
AU  - Hu Z
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Keskin, Derin B
AU  - Keskin DB
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Shukla, Sachet A
AU  - Shukla SA
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Sun, Jing
AU  - Sun J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Bozym, David J
AU  - Bozym DJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Zhang, Wandi
AU  - Zhang W
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Luoma, Adrienne
AU  - Luoma A
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, Massachusetts 02215, USA.
FAU - Giobbie-Hurder, Anita
AU  - Giobbie-Hurder A
AD  - Department of Biostatistics and Computational Biology, Dana-Farber Cancer 
      Institute, Boston, Massachusetts 02215, USA.
FAU - Peter, Lauren
AU  - Peter L
AD  - Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 
      Boston, Massachusetts 02215, USA.
AD  - Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA.
FAU - Chen, Christina
AU  - Chen C
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Olive, Oriol
AU  - Olive O
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Carter, Todd A
AU  - Carter TA
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Li, Shuqiang
AU  - Li S
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Lieb, David J
AU  - Lieb DJ
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Eisenhaure, Thomas
AU  - Eisenhaure T
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Gjini, Evisa
AU  - Gjini E
AD  - Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Stevens, Jonathan
AU  - Stevens J
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
FAU - Lane, William J
AU  - Lane WJ
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
FAU - Javeri, Indu
AU  - Javeri I
AD  - CuriRx, Inc., Wilmington, Massachusetts 01887, USA.
FAU - Nellaiappan, Kaliappanadar
AU  - Nellaiappan K
AD  - CuriRx, Inc., Wilmington, Massachusetts 01887, USA.
FAU - Salazar, Andres M
AU  - Salazar AM
AD  - Oncovir, Inc., 3203 Cleveland Avenue, NW, Washington DC 20008, USA.
FAU - Daley, Heather
AU  - Daley H
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Seaman, Michael
AU  - Seaman M
AD  - Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 
      Boston, Massachusetts 02215, USA.
FAU - Buchbinder, Elizabeth I
AU  - Buchbinder EI
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
FAU - Yoon, Charles H
AU  - Yoon CH
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02215, 
      USA.
FAU - Harden, Maegan
AU  - Harden M
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Lennon, Niall
AU  - Lennon N
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Gabriel, Stacey
AU  - Gabriel S
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Rodig, Scott J
AU  - Rodig SJ
AD  - Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
FAU - Barouch, Dan H
AU  - Barouch DH
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, 
      Boston, Massachusetts 02215, USA.
AD  - Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA.
FAU - Aster, Jon C
AU  - Aster JC
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
FAU - Getz, Gad
AU  - Getz G
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Wucherpfennig, Kai
AU  - Wucherpfennig K
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 
      Boston, Massachusetts 02215, USA.
FAU - Neuberg, Donna
AU  - Neuberg D
AD  - Department of Biostatistics and Computational Biology, Dana-Farber Cancer 
      Institute, Boston, Massachusetts 02215, USA.
FAU - Ritz, Jerome
AU  - Ritz J
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
FAU - Lander, Eric S
AU  - Lander ES
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Fritsch, Edward F
AU  - Fritsch EF
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
FAU - Hacohen, Nir
AU  - Hacohen N
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
FAU - Wu, Catherine J
AU  - Wu CJ
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 
      Massachusetts 02215, USA.
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 
      02215, USA.
AD  - Harvard Medical School, Boston, Massachusetts 02215, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
LA  - eng
GR  - P50 CA101942/CA/NCI NIH HHS/United States
GR  - R01 HL103532/HL/NHLBI NIH HHS/United States
GR  - R50 CA211482/CA/NCI NIH HHS/United States
GR  - R01 CA155010/CA/NCI NIH HHS/United States
GR  - T32 CA207021/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170705
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - DPT0O3T46P (pembrolizumab)
SB  - IM
CIN - Nature. 2017 Jul 13;547(7662):165-167. PMID: 28678783
CIN - Nat Rev Cancer. 2017 Jul 25;17 (8):451. PMID: 28740114
CIN - Immunity. 2017 Aug 15;47(2):221-223. PMID: 28813655
CIN - Trends Mol Med. 2017 Oct;23 (10 ):869-871. PMID: 28867556
EIN - Nature. 2018 Mar 14;555(7696):402. PMID: 29542692
MH  - Amino Acid Sequence
MH  - Antibodies, Monoclonal, Humanized/pharmacology/therapeutic use
MH  - Antigens, Neoplasm/chemistry/*genetics/*immunology
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - CD8-Positive T-Lymphocytes/immunology
MH  - Cancer Vaccines/adverse effects/chemistry/*immunology
MH  - High-Throughput Nucleotide Sequencing
MH  - Histocompatibility Antigens Class II/immunology
MH  - Humans
MH  - Machine Learning
MH  - Melanoma/genetics/*immunology/*therapy
MH  - Mutation
MH  - Neoplasm Recurrence, Local/immunology/prevention & control
MH  - Patient Safety
MH  - Precision Medicine/*methods
MH  - Programmed Cell Death 1 Receptor/antagonists & inhibitors
PMC - PMC5577644
MID - NIHMS892660
COIS- Competing Financial Interests (Online only) 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 the 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 Tumor 
      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 Inc. The 
      remaining authors declare no competing financial interests.
EDAT- 2017/07/06 06:00
MHDA- 2017/12/06 06:00
PMCR- 2018/01/13
CRDT- 2017/07/06 06:00
PHST- 2017/02/16 00:00 [received]
PHST- 2017/05/16 00:00 [accepted]
PHST- 2017/07/06 06:00 [pubmed]
PHST- 2017/12/06 06:00 [medline]
PHST- 2017/07/06 06:00 [entrez]
PHST- 2018/01/13 00:00 [pmc-release]
AID - nature22991 [pii]
AID - 10.1038/nature22991 [doi]
PST - ppublish
SO  - Nature. 2017 Jul 13;547(7662):217-221. doi: 10.1038/nature22991. Epub 2017 Jul 5.