Vaccination of patients against mostly patient-specific neoantigens 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 propose to develop a broadly applicable vaccination strategy against a common set of predefined antigens that are experimentally induced in tumor cells by downregulation of key mediators of antigen processing pathway, TAP, ERAAP and Invariant chain (Ii). Genetic ablation of TAP or ERAAP leads to the presentation of class I- restricted neoepitopes that are capable of stimulating T cell responses and inhibit the growth of TAP or ERAAP deficient tumor cells whereas downregulation of Invariant chain (Ii) leads to the presentation of otherwise cryptic endogenous class II epitopes. Vaccination against the TAP, ERAAP or Ii downregulation-induced antigens will constitute a broadly applicable neoantigen-targeted vaccination strategy for patients with concurrent, recurrent, and future tumors that overcomes the main limitations of vaccinating against mutation- generated patient-specific neoantigens. Proposal is supported by our studies showing that vaccination against the TAP downregulation-induced antigens, by targeting a TAP siRNA to resident DC in mice thru conjugation to a CpG oligonucleotide (CpG- TAP siRNA), was more effective than vaccination against prototypic patient-specific mutation-generated neoantigens, was devoid of measurable toxicity, and inhibited the growth of concurrent and future tumors in models of recurrence and premalignant disease, provided TAP was also downregulated in the developing tumors using a broad-range nucleolin binding aptamer to target the TAP siRNA to tumor cells in situ (Nucl-TAP siRNA). The goal of this proposal is to optimize the induced neoantigen vaccination strategy in order to set the stage for its evaluation in clinical trials: (1). To develop optimal methods to induce neoantigens by inhibiting key mediators of antigen processing, TAP, ERAAP, and Ii. We hypothesize that given the synergy between CD4+ and CD8+ T cell immunity, TAP or ERAAP downregulation that elicit CD8+ T cell responses combined with Ii downregulation that elicit CD4+ T cell responses will be the most effective combinations. (2) To evaluate combinations with cell-targeted immune potentiating modalities. We will test two novel tumor- and T cell-targeted strategies, to sensitize tumors to a proinflammatory immune response, i.e. convert ?cold? to ?hot? tumor lesions, and to promote the intratumoral accumulation of tumor- resident CD8+ T cells (Trm), respectively. (3) Develop lead compounds for clinical trials. Identify the best- in-class targets, TAP, ERAAP, Ii, or combination of, to stimulate human CD8+ T cell responses in vitro using CpG-siRNA treated DC, that will recognize tumor cells treated with Nucl-siRNA to induce the presentation of said antigens on the tumor cells.
|Effective start/end date||8/1/21 → 7/31/22|
- National Cancer Institute: $351,131.00
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