Journal Article

Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients

Mardis, Elaine R., Miller, Christopher A., Myers, Nancy B., Griffith, Obi, Hagemann, Ian S., Vickery, Tammi, McLellan, Michael D., Foluso, Ademuyiwa, Chen, Michael Y., Li, Lijin, Gao, Feng, Davidson, Jesse T., Yu, Yik Yeung, Suresh, Rama, Goedegebuure, S. Peter, Sankpal, Narendra V., Schreiber, Robert D., Hansen, Ted H., Zhang, Xiuli, Griffith, Malachi, Singhal, Kartik, Gillanders, William E., Zhang, Felicia, Hundal, Jasreet, Ma, Cynthia X., Chen, Ina, Mishra, Rashmi, Myles, Stephanie, Wang-Gillam, Andrea, Sturmoski, Mark A., Davies, Sherri, Fleming, Timothy P., Kim, Samuel W.

2024

Overview

Background Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence. Methods Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing. Results Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4–20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7–100%) in the cohort of vaccinated patients. Conclusion Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses. Clinical trial registration number NCT02348320.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Aged / Algorithms / Amino acids / Antigenic determinants / Antigens, Neoplasm - genetics / Antigens, Neoplasm - immunology / Antitumor activity / Autoimmunity / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Breast cancer / Cancer / Cancer patients / Cancer Research / Cancer vaccines / Cancer Vaccines - adverse effects / Cancer Vaccines - immunology / Cancer Vaccines - therapeutic use / Chemotherapy / Clinical trial / Clinical trials / Deoxyribonucleic acid / Diseases / DNA / DNA Vaccine / DNA vaccines / Electroporation / Enzyme-linked immunosorbent assay / Epitopes / Female / Flow cytometry / Gene amplification / Genetic testing / Human Genetics / Humans / Immune response / Immune system / Immunity (Disease) / Industrial design / Integrated software / Lymphocytes / Lymphocytes T / Medical colleges / Medical research / Medicine, Experimental / Medicine/Public Health / Melanoma / Metabolomics / Middle Aged / Mutation / Neoantigen / Neoantigens / Patients / Peptides / Phase I / Relapse / Risk assessment / RNA / RNA sequencing / Systems Biology / T cells / TNBC / Triple Negative Breast Neoplasms - immunology / Tumor antigens / Tumors / Vaccination / Vaccines / Vaccines, DNA - immunology / Whole genome sequencing