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

A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma (Cell, 2025) Eryn Blass1,5,17, Derin B. Keskin1, 3, 4, 5, 6, 7,17, Chloe R. Tu1, 2, Cleo Forman1, 2, Allison Vanasse3, Haley E. Sax1, Bohoon Shim2, Vipheaviny Chea3, Nawoo Kim3, Isabel Carulli3, Jackson Southard3, Haoxiang Lyu3, Wesley Lu3, 16, Micah Rickles-Young4, Alexander B. Afeyan1, 5, Oriol Olive1, Ambica Mehndiratta1, Haley Greenslade1, Keerthi Shetty1, Joanna Baginska1, 8, Ilana Gomez Diaz1, 8, Allison Nau2, 8, Kathleen L. Pfaff8, Andrew Gans8, Srinika Ranasinghe8, Elizabeth I. Buchbinder1, 5, 9, Tamara A. Sussman1, 5, 9, Megan L Insco1, 5, 9, Charles H. Yoon1, 5, 10, Scott J. Rodig5,11, Sachet A. Shukla3,16, Shuqiang Li1,3,4 , Jon C. Aster5, 11, David A. Braun1, 12, 13, Carrie Cibulskis4, Nir Hacohen4, 5, 14, Donna S. Neuberg2, Anita Giobbie-Hurder2, Kenneth J. Livak3, Edward F. Fritsch1, 4, Giacomo Oliveira1,4,5, Jeremy M. Simon2, 15, Catherine J. Wu1, 4, 5, 9, Patrick A. Ott1, 4, 5, 8, 9, 18,* Affiliations: 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA 2 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA 3 Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, 02215, USA 4 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA 5Harvard Medical School, Boston, MA, 02215, USA 6Department of Computer Science, Metropolitan College, Boston University, Boston, MA, 02215, USA 7Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, 2800 Lyngby, Denmark. 8 Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA 9Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 02215, USA 10 Department of Surgery, Brigham and Women’s Hospital, Boston, MA, 02215, USA 11 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02215, USA 12 Section of Medical Oncology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA 13Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06511, USA 14 Massachusetts General Hospital, Krantz Family Center for Cancer Research, Boston, MA, 02114 USA 15 Department of Biostatistics, Harvard T.H. Chan School of Public Health, 02215, USA 16 Current address: Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA 17 These authors contributed equally 18 Lead Contact *Correspondence: [e-mail] (P.A.O) 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. This repository contains supplementary data files 1-5: Data S1, List of patient mutations, related to Figure 1 Data S2, Supporting vaccine-site single-cell analysis data, related to Figure 2 Data S3, Supporting bulk-TCR clonotype analysis data, related to Figure 3 Data S4, Supporting tumor single-cell analysis data, related to Figure 4 Data S5, Supporting single-cell data for TCR reactivity assessment, related to Figure 5