Abstract B111: Vaccination against TAP downregulation-induced neoantigens to prevent future tumor development in the setting of recurrence or premalignancy

• Published in: Cancer immunology research 2019-02, Vol.7 (2_Supplement), p.B111-B111
• Main Authors: Hidalgo, Greta Garrido, Schrand, Brett, Rabasa, Ailem, Levay, Agata, Gefen, Tal, Bhuwan, Giri Bhuwan, Ferrantella, Anthony R., Dudeja, Vikas, Marijt, Koen, Hall, Thorbald T. van, Gilboa, Eli
• Format: Article
• Language: English
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6074.CRICIMTEATIAACR18-B111

Development of therapeutic strategies to prevent recurrence in cancer patients, or tumor progression in individuals at high risk of developing cancer, has been challenging given the long and often unpredictable time to the emergence of the malignant tumors. Mutation-generated 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.To overcome the limitations of targeting mutated neoantigens, we have developed a simple and broadly applicable approach to induce neoantigens in tumor cells in situ by reducing the expression of peptide transporter TAP, whereby a TAP-specific siRNA is targeted to tumor cells in mice by conjugation to a broad-range nucleolin-binding aptamer. Nucleolin, normally expressed in the cytoplasm and nucleolus of all somatic cells, is translocated to the cell surface of most murine and human tumors and hence could serve as an almost universal target to deliver therapeutics to tumors in vivo. Previous results have demonstrated that genetic ablation of TAP not only inhibits the canonical antigen processing pathway but also upregulates alternative pathways presenting new epitopes, essentially neoantigens, that can be recognized by the immune system to elicit effective CD8+ T-cell responses. Such epitopes are shared among all (tumor) cells in which TAP is downregulated, corresponding to the functional equivalent of clonal mutation-generated neoantigens. Our study shows that transiently increasing the neoantigen burden of tumor cells in situ by targeted downregulation of TAP represent a potent way of generating antitumor immunity in the absence of measurable toxicity.Exploiting the ability to induce neoantigens in situ, we are developing a novel vaccination strategy targeting potent neoantigens to control the growth of the future tumors—whereby mice in remission or with premalignant lesions are first vaccinated against TAP downregulation-induced neoantigens, and when or if tumor develops the same antigens are induced in the tumor, termed prorapeutic vaccination (prophylactic + therapeutic). To induce an immune response against TAP downregulation-induced neoantigens, mice were vaccinated with TAP siRNAs that are targeted to DC in situ by conjugation to a short CpG oligonucleotide leading to the downregulation of TAP, expression of neoantigens, as well as activation of the DC, and thereby priming of a potent T-cell res