Abstract
Abstract Vaccination of patients against mostly patient-specific neoantigens expressed in concurrent and recurring tumors, or tumors developing in individuals at high risk of cancer, is posing major challenges in terms of which antigens to target and is limited to a subset of patients expressing neoantigens in their tumors. Here we describe a broadly applicable vaccination strategy against shared antigens that are experimentally induced in tumor cells by downregulation of the peptide transporter TAP. Presentation of the new epitopes in tumor cells is achieved using a siRNA to downregulate TAP mRNA, which is targeted to tumor cells in situ by conjugation to a broad-range nucleolin binding oligonucleotide aptamer ligand. An immune response against the TAP downregulation-induced antigens presented by the tumor cells is elicited by downregulation of TAP in resident dendritic cells via conjugation to a CpG oligonucleotide. Vaccination against experimentally induced antigens is particularly suitable for vaccination against tumors that recur after a long period of remission, or tumors that will develop in individuals at high risk of cancer, because it eliminates the uncertainties of which neoantigens are expressed in the future tumors. Vaccination against the TAP downregulation-induced antigens was more effective than vaccination against tumor-resident, mutation-generated, shared neoantigens, was devoid of measurable toxicity, and inhibited the growth of future tumors in models of recurrence and premalignant disease. Human CD8+ T cells stimulated with TAPlow dendritic cells elicited a polyclonal CD8+ T-cell response that recognized tumor cells with experimentally reduced TAP expression, as well as CMV and EBV infected cells that naturally downregulate TAP expression. Vaccination against TAP downregulation-induced antigens overcomes the main limitations of vaccinating against mostly unique tumor-resident neoantigens and could represent a common vaccination strategy for patients with concurrent, recurrent, and future tumors. Citation Format: Greta Garrido, Brett Schrand, Agata Levay, Ailem Rabasa, Anthony Ferrantella, Diane Da Silva, Francesca D’Eramo, Koen Marijt, Lisa Daley-Bauer, Deukwoo Kwon, Martin Kast, Ed Mocarski, Vikas Dudeja, Thorbald van Hall, Eli Gilboa. Prorapeutic vaccination against shared antigens induced in future tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B26.