Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy

Development of therapeutic strategies to prevent recurrence in cancer patients, or tumor progression in at risk individuals has been challenging given the long and often unpredictable time to the emergence of the malignant tumors. Neoantigens represent the most potent antigens to induce antitumor immunity, yet the ability to predict which neoantigens will be expressed in future tumors is at present not an option. We have developed a simple and broadly applicable approach to induce neoantigens in tumor cells in situ by reducing the expression of antigen processing mediators like TAP, ERAAP, or invariant chain (Ii), using siRNAs that were targeted to tumor cells by conjugation to a nucleolin-binding aptamer. Exploiting the ability to induce neoantigens in situ, we describe a novel vaccination strategy targeting potent neoantigens to control the growth of the future tumors whereby patients in remission or individuals at risk are first vaccinated against the antigen processing downregulation-induced neoantigens and when or if tumor develops the same antigens are induced in the tumor, termed prorapeutic vaccination (prophylactic + therapeutic). Mice were vaccinated against the TAP downregulation-induced neoantigens by targeting the corresponding siRNAs to dendritic cells (DC) in situ via conjugation to a short CpG oligonucleotide (ODN); the CpG ODN also activated the targeted DC to avoid induction of tolerance against the neoantigens. Vaccination with CpG ODN-TAP siRNA conjugates inhibited subsequently implanted or autochthonous tumors in several tumor models, provided the said neoantigens were also induced in the tumor by nucleolin aptamer-targeted siRNA inhibition of TAP. The CpG-siRNA and nucleolin aptamer-siRNA conjugates are simple, chemically- synthesized, off-the-shelf, and broadly applicable reagents to vaccinate against neoantigens and control the growth of future tumors irrespective of their origin. Citation Format: Greta Garrido Hidalgo, Brett Schrand, Ailem Rabasa, Agata Levay, Alexey Berezhnoy, Shrey Modi, Giri Bhuwan Bhuwan, Vikas Dudeja, Elien Doorduijn, Thorbald van Hall, Eli Gilboa. Vaccination against neoantigens induced in future tumors in the setting of recurrence and premalignancy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 264.