Synthetic long peptide vaccines possessing a universal helper epitope can unmask the therapeutic effects of MHC I-restricted neoepitopes

• Published in: The Journal of immunology (1950) 2020-05, Vol.204 (1_Supplement), p.91-91.26
• Main Authors: Swartz, Adam, Riccione, Katherine, Congdon, Kendra, Sanchez-Perez, Luis A, Nair, Smita K, Sampson, John H
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.91.26

Synthetic long peptide (SLP) vaccines targeting neoantigens arising from patient-specific missense mutations may offer a means to address the antigenic heterogeneity of glioblastoma (GBM) tumors by simultaneously targeting a multitude of tumor-specific antigens expressed throughout these heterogenous tumors. This approach is challenged by uncertainties pertaining to vaccine design, including peptide composition required for immunogenicity and efficacy. To this end, we investigated the mechanism of an efficacious SLP vaccine targeting the neoantigen Odc1, expressed within the mouse astrocytoma SMA560. This led to the identification of three generalizable principles governing the effectiveness of neoantigen-targeting SLPs: (1) SLPs containing an MHC I-restricted neoepitope may activate neoantigen-reactive CD8+ T cells, which drive direct antitumor effects; (2) to induce robust neoantigen-reactive CD8+ T-cell responses, CD40L-mediated T cell "help" is required; and, (3) CD40L interactions are conferred by an SLP only when a “helper” epitope is physically conjoined to an MHC I-restricted neoepitope. To leverage these findings for clinical translation, we developed a rationally-designed vaccine comprised of an MHC I-restricted neoepitope linked to a universal “helper” epitope. This design was capable of maintaining the effects of the Odc1 vaccine and, remarkably, unmasked the therapeutic effects of, otherwise, poorly immunogenic MHC I-restricted neoepitopes. Together, these findings are significant because they elucidate mechanisms required for efficacious SLP vaccines and demonstrate a clinically-tractable approach with the potential to expand the therapeutic breadth of neoantigen vaccines.