Personal Neoantigen Vaccines Induce Persistent Neoantigen-Specific Memory T Cell Responses and Epitope Spreading in High-Risk Melanoma Patients

Abstract

Cancer vaccines have long been envisioned as an effective approach to generate, amplify and diversify T cell responses against tumors. The recent availability of next-generation sequencing (NGS) has enabled the comprehensive identification of mutations within a patient’s tumor, which represent an abundant source of tumor-specific potential antigens. Tumor neoantigens, altered peptides generated from somatic mutations in tumor cells, are promising therapeutic targets due to their exquisite tumor specificity and exemption from central tolerance mechanisms. Notably, highly effective antitumor responses have been associated with the presence of neoantigen-specific T cells. Recently, the Wu lab and others have demonstrated that personalized neoantigen-targeting vaccines are safe, feasible and highly immunogenic in phase I trial of stage III/IV resected high-risk melanoma1,2. The Wu lab’s neoantigen vaccine (NeoVax), consisting of up to 20 long peptides and poly-ICLC, induced strong polyfunctional neoantigen-specific T-cells that recognized patient tumors in vitro. In addition, two patients who were vaccinated and received anti-PD-1 checkpoint blockade (CPB) therapy upon relapse had durable complete responses (CRs). To define the long-term effects of a therapeutic vaccine directed against personal tumor neoantigens, we evaluated the clinical outcomes and circulating immune responses of eight patients with high-risk melanoma, at a median of 50.5 and 46 months, respectively, after initiation of treatment with NeoVax. All patients remain alive, and 6 of 8 are currently without evidence of disease. In the current study, we report consistent long-term persistence of neoantigen-specific T cell responses following vaccination, ex vivo detection of neoantigen-specific T cells with a memory phenotype, expansion and diversification of neoantigen-specific T cell clones over time, and epitope spreading, indicating on-target vaccine-induced tumor destruction. These data demonstrate that personalized neoantigen peptide vaccines durably induce T cell responses in melanoma patients over the course of years, broadening the spectrum of tumor-specific cytotoxicity and contributing to enduring immunoprotection.