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

Eryn Blass; Derin B Keskin; Chloe R Tu; Cleo Forman; Allison Vanasse; Haley E Sax; Bohoon Shim; Vipheaviny Chea; Nawoo Kim; Isabel Carulli; Jackson Southard; Haoxiang Lyu; Wesley Lu; Micah Rickles-Young; Alexander B Afeyan; Oriol Olive; Ambica Mehndiratta; Haley Greenslade; Keerthi Shetty; Joanna Baginska; Ilana Gomez Diaz; Allison Nau; Kathleen L Pfaff; Andrew Gans; Srinika Ranasinghe; Elizabeth I Buchbinder; Tamara A Sussman; Megan L Insco; Charles H Yoon; Scott J Rodig; Sachet A Shukla; Shuqiang Li; Jon C Aster; David A Braun; Carrie Cibulskis; Nir Hacohen; Donna S Neuberg; Anita Giobbie-Hurder; Kenneth J Livak; Edward F Fritsch; Giacomo Oliveira; Jeremy M Simon; Catherine J Wu; Patrick A Ott

doi:10.1016/j.cell.2025.06.019

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

Cell. 2025 Sep 18;188(19):5125-5141.e27. doi: 10.1016/j.cell.2025.06.019. Epub 2025 Jul 10.

Authors

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

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.

Publication types

Clinical Trial, Phase I

MeSH terms

Adjuvants, Immunologic*
Antigens, Neoplasm* / immunology
CD8-Positive T-Lymphocytes / immunology
Cancer Vaccines* / immunology
Cancer Vaccines* / therapeutic use
Female
Humans
Ipilimumab / therapeutic use
Male
Melanoma* / immunology
Melanoma* / therapy
Middle Aged
Nivolumab / therapeutic use
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / metabolism

Substances

Cancer Vaccines
Antigens, Neoplasm
Ipilimumab
Nivolumab
Adjuvants, Immunologic
Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding