Abstract
Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient (NCT01970358). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 515-525 |
| Number of pages | 11 |
| Journal | Nature medicine |
| Volume | 27 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2021 |
| Externally published | Yes |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
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In: Nature medicine, Vol. 27, No. 3, 03.2021, p. 515-525.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma
AU - Hu, Zhuting
AU - Leet, Donna E.
AU - Allesøe, Rosa L.
AU - Oliveira, Giacomo
AU - Li, Shuqiang
AU - Luoma, Adrienne M.
AU - Liu, Jinyan
AU - Forman, Juliet
AU - Huang, Teddy
AU - Iorgulescu, J. Bryan
AU - Holden, Rebecca
AU - Sarkizova, Siranush
AU - Gohil, Satyen H.
AU - Redd, Robert A.
AU - Sun, Jing
AU - Elagina, Liudmila
AU - Giobbie-Hurder, Anita
AU - Zhang, Wandi
AU - Peter, Lauren
AU - Ciantra, Zoe
AU - Rodig, Scott
AU - Olive, Oriol
AU - Shetty, Keerthi
AU - Pyrdol, Jason
AU - Uduman, Mohamed
AU - Lee, Patrick C.
AU - Bachireddy, Pavan
AU - Buchbinder, Elizabeth I.
AU - Yoon, Charles H.
AU - Neuberg, Donna
AU - Pentelute, Bradley L.
AU - Hacohen, Nir
AU - Livak, Kenneth J.
AU - Shukla, Sachet A.
AU - Olsen, Lars Rønn
AU - Barouch, Dan H.
AU - Wucherpfennig, Kai W.
AU - Fritsch, Edward F.
AU - Keskin, Derin B.
AU - Wu, Catherine J.
AU - Ott, Patrick A.
N1 - Funding Information: The authors thank J. Russell, M. Manos, M. Severgnini and the Center for Immuno-Oncology staff, M. Copersino (Regulatory Affairs), B. Meyers, C. Harvey and S. Bartel (Clinical Pharmacy), M. Bowden (Center for Molecular Oncologic Pathology), O. Sturtevant, H. Negre, S.Y. Kim and M.A. Kelley (Cell Manipulation Core Facility), the Pasquarello Tissue Bank (all at DFCI), T. Bowman (DFHCC Specialized Histopathology Core Laboratory), M. Harden, N. Lennon, S. Gabriel, S. Pollack (the Broad Institute’s Biological Samples, Genetic Analysis and Genome Sequencing Platform), J. Ritz (DFCI) and I. Leshchiner, G. Getz (Broad Institute), for discussions. This research was made possible by a generous gift from the Blavatnik Family Foundation, and was supported by grants from the National Institutes of Health (NIH/NCI (R21 CA216772-01A1 and NCI-SPORE-2P50CA101942-11A1 (to D.B.K.); U24CA224331 and R01CA155010 (to C.J.W.); NCI-R50 RCA211482A (to S.A.S.)); NCI-R50 CA251956 (to S.L.); NCI-R01 CA229261 (to P.A.O.); NCI P01 CA163222; NCI-R01 CA238039 (to K.W.W.); 5P30 CA006516 (to A.G.H., R.R. and D.N.) and NCI-K12CA090354 (to J.B.I.)); a Team Science Award from the Melanoma Research Alliance (to C.J.W. and P.A.O.); 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.); the Bender Family Research Fund (to P.A.O.), and the DFCI Center for Cancer Immunotherapy Research fellowship and 5 T32 CA 207021-3 (to Z.H. and A.M.L.); a Physician-Scientist Training Award from the Damon Runyon Cancer Research Foundation (to P.B.); an Amy Strelzer Manasevit Scholar Award from the Be The Match Foundation (to P.B.); an American Society of Hematology Fellow Scholar Award (to P.B.); an NSF Graduate Research Fellowships Program fellowship (to R.H.); a Kay Kendall Leukaemia Fund Fellowship (to S.H.G.). L.R.O. is funded by The Free Research Fund Denmark (8048-00078A). C.J.W. is a scholar of the Leukemia and Lymphoma Society. We also acknowledge a gift from a donor to the Developing Innovative Immunological Therapies for Intractable Cancers Fund. This work was further supported in part by The G. Harold and Leila Y. Mathers Foundation and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center, the Howard Hughes Medical Institute Medical Research Fellows Program and the Novo Nordisk Foundation (grant agreement NNF14CC0001). Funding Information: Z.H. is a current employee of ElevateBio. J.S. is a current employee of Moderna Therapeutics. E.F.F. is an equity holder and consultant for BioNTech, and equity holder and SAB member of BioEntre. N.H. and C.J.W. are equity holders of BioNTech. N.H. is a consultant for Related Sciences. P.A.O. has received research funding from and has advised Neon Therapeutics, Bristol-Meyers Squibb, Merck, CytomX, Pfizer, Novartis, Celldex, Amgen, Array, AstraZeneca/MedImmune, Armo BioSciences and Roche/ Genentech. C.J.W. is subject to a conflict of interest management plan for the reported studies because of her former competing financial interests in Neon Therapeutics, which was acquired by BioNTech. Under this plan, C.J.W. may not access identifiable data for human subjects or otherwise participate directly in the Institutional Review Board-approved protocol reported herein. C.J.W.’s contributions to the overall strategy and data analyses occurred on a de-identified basis. 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 neoantigens’ (N.H. and C.J.W.), ‘Formulations for neoplasia vaccines’ (E.F.F.) and ‘Combination therapy for neoantigen vaccine’ (N.H., C.J.W. and E.F.F.). The DFCI, the lead site of this trial, has a proprietary and financial interest in the personalized neoantigen vaccine. P.B. reports equity in Agenus, Amgen, Breakbio Corp., Johnson & Johnson, Exelixis and BioNTech. S.J.R. receives research support from Merck, Bristol Myers Squibb, Affimed and KITE/Gilead, and is on a scientific advisory board for Immunitas Therapeutics. S.A.S. reported nonfinancial support from Bristol-Myers Squibb outside the submitted work. S.A.S. also previously advised and has received consulting fees from Neon Therapeutics and reported equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol-Myers Squibb and Lumos Pharma, outside the submitted work. B.L.P. is a founder of Resolute Bio and Amide Technologies; both companies develop protein and peptide therapeutics. E.I.B. consults for Apexigen, Novartis, Partner Therapeutics and receives clinical trial support from Eli Lilly, Novartis, BMS, Genentech and BVD. K.W.W. serves on the scientific advisory board of TCR2 Therapeutics, T-Scan Therapeutics, SQZ Biotech, Nextechinvest and receives sponsored research funding from Novartis. He is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication. D.B.K. has previously advised Neon Therapeutics and has received consulting fees from Neon Therapeutics. D.B.K. also owns equity in Aduro Biotech, Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceutical, Bristol Myers Squibb, Celldex Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Moderna and Regeneron Pharmaceuticals. BeiGene, a Chine biotech company, supports unrelated research at the Translational Immunogenomics Laboratory. The remaining authors declare no competing interests. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/3
Y1 - 2021/3
N2 - Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient (NCT01970358). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
AB - Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient (NCT01970358). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
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U2 - 10.1038/s41591-020-01206-4
DO - 10.1038/s41591-020-01206-4
M3 - Article
C2 - 33479501
AN - SCOPUS:85099906914
SN - 1078-8956
VL - 27
SP - 515
EP - 525
JO - Nature medicine
JF - Nature medicine
IS - 3
ER -