A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma

Eryn Blass¹, Derin B Keskin², Chloe R Tu³, Cleo Forman³, Allison Vanasse⁴, Haley E Sax⁵, Bohoon Shim⁶, Vipheaviny Chea⁴, Nawoo Kim⁴, Isabel Carulli⁴, Jackson Southard⁴, Haoxiang Lyu⁴, Wesley Lu⁴, Micah Rickles-Young⁷, Alexander B Afeyan¹, Oriol Olive⁵, Ambica Mehndiratta⁵, Haley Greenslade⁵, Keerthi Shetty⁵, Joanna Baginska⁸, Ilana Gomez Diaz⁸, Allison Nau⁹, Kathleen L Pfaff¹⁰, Andrew Gans¹⁰, Srinika Ranasinghe¹⁰, Elizabeth I Buchbinder¹¹, Tamara A Sussman¹¹, Megan L Insco¹¹, Charles H Yoon¹², Scott J Rodig¹³, Sachet A Shukla⁴, Shuqiang Li¹⁴, Jon C Aster¹³, David A Braun¹⁵, Carrie Cibulskis⁷, Nir Hacohen¹⁶, Donna S Neuberg⁶, Anita Giobbie-Hurder⁶, Kenneth J Livak⁴, Edward F Fritsch¹⁷, Giacomo Oliveira¹⁸, Jeremy M Simon¹⁹, Catherine J Wu²⁰, Patrick A Ott²¹

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Computer Science, Metropolitan College, Boston University, Boston, MA 02215, USA; Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, 2800 Lyngby, Denmark.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹³ Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital, Krantz Family Center for Cancer Research, Boston, MA 02114, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.
¹⁹ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
²⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
²¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: patrick_ott@dfci.harvard.edu.

PMID: 40645179
PMCID: PMC12351686 (available on 2026-07-10)
DOI: 10.1016/j.cell.2025.06.019

Clinical Trial

A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma

Eryn Blass et al. Cell. 2025.

. 2025 Sep 18;188(19):5125-5141.e27.

doi: 10.1016/j.cell.2025.06.019. Epub 2025 Jul 10.

Authors

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Computer Science, Metropolitan College, Boston University, Boston, MA 02215, USA; Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, 2800 Lyngby, Denmark.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁶ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁹ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹³ Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Massachusetts General Hospital, Krantz Family Center for Cancer Research, Boston, MA 02114, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA.
¹⁹ Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02215, USA.
²⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
²¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: patrick_ott@dfci.harvard.edu.

PMID: 40645179
PMCID: PMC12351686 (available on 2026-07-10)
DOI: 10.1016/j.cell.2025.06.019

Abstract

Personalized neoantigen-targeting vaccines have demonstrated great promise; however, improved immunogenicity is still needed. Since antigen availability and effective T cell priming are critical for maximal immunogenicity, we tested a synthetic long peptide vaccine formulated with Montanide, poly-ICLC, and locally administered ipilimumab in addition to systemic nivolumab in 10 patients with melanoma. These personalized vaccines generated de novo ex vivo T cell responses against the majority of immunizing neoepitopes in all 9 fully vaccinated patients and ex vivo CD8+ T cell responses in 6 of 9. Vaccination induced hundreds of circulating and intratumoral T cell receptor (TCR) clonotypes that were distinct from those arising after PD-1 inhibition. By linking the vaccine neoantigen specificity of T cell clonotypes with single-cell phenotypes in tumors, we demonstrate remodeling of the intratumoral T cell repertoire following vaccination. These observations show that multi-pronged immune adjuvanticity can boost T cell responses to neoantigen-targeting vaccines.

Keywords: T cell; cancer vaccines; immunotherapy; melanoma; mutation; neoantigen; personalized; vaccine.

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Conflict of interest statement

Declaration of interests D.B.K. owns equity in Affimed N.V., Agenus, Armata Pharmaceuticals, Breakbio, BioMarin Pharmaceuticals, Celldex Therapeutics, Editas Medicine, Immunitybio, Lexicon Pharmaceuticals, Moderna, Summit Therapeutics, and Viking Therapeutics. D.B.K. is a scientific advisor for Immunitrack, a wholly owned subsidiary of Eli Lilly and Company and Breakbio. D.A.B. reports share options in Elephas; advisory board, consulting, or personal fees from Cancer Expert Now, Adnovate Strategies, MDedge, CancerNetwork, Catenion, OncLive, Cello Health BioConsulting, PWW Consulting, Haymarket Medical Network, Aptitude Health, ASCO Post and Harborside, Targeted Oncology, Merck, Pfizer, MedScape, Accolade 2nd MD, DLA Piper, AbbVie, Compugen, Link Cell Therapies, Scholar Rock, NeoMorph, Nimbus, Exelixis, AVEO, Eisai, and Elephas; and research support from Exelixis and AstraZeneca, outside of the submitted work.S.A.S. reports equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol-Myers Squibb, Imunon, Jivanu Therapeutics, and Lumos Pharma. S.A.S. reports advisory or consulting roles for Imunon and Jivanu Therapeutics. N.H. holds equity in and advises Danger Bio/Related Sciences and Repertoire Immune Medicines, owns equity in BioNtech, and receives research funding from Bristol-Myers Squibb and Calico Life Sciences. E.F.F. is an equity holder in and consultant for BioNTech, an equity holder and scientific advisory board member of BioEntre, and a founder and equity holder of Dionis Therapeutics. 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 site of this trial, has a proprietary and financial interest in the personalized neoantigen vaccine. P.A.O. has received research funding from and/or has advised Agenus, Arcturus, Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol-Meyers Squibb, Celldex, CytomX, Evaxion, Immunetune, Imunon, LGChem, Merck, Neon Therapeutics (now BioNTechUS), Novartis, Pharmajet, Phio, Pfizer, Oncorus, Roche/Genentech, Servier, and Xencor.

References

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A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma

Affiliations

A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma

Authors

Affiliations

Abstract

Conflict of interest statement

References

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