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Vaccination against antigens induced by TAP downregulation in concurrent and future tumors

针对当前和未来肿瘤中 TAP 下调诱导的抗原的疫苗接种

基本信息

批准号：
10664957
负责人：
Eli Gilboa
金额：
$ 34.41万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664957
关键词：
Ablation Antigens Autoimmune Binding CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CPG-oligonucleotide Cancer Vaccines Cells Clinical Trials Development Disease Disease remission Down-Regulation Drug Delivery Systems Epitopes Evaluation Future Genetic Genetic Predisposition to Disease Goals Growth Human Immune Immune Targeting Immune response Immunity Immunotherapy Impairment In Situ In Vitro Individual Inflammatory Intervention Lead Lesion MHC Class I Genes Malignant Neoplasms Measurable Mediator Methods Modality Modeling Mus Mutation Neoplasm Metastasis Nucleic Acids Oligonucleotides Pathology Pathway interactions Patients Peptides Pharmaceutical Preparations Predisposition Procedures Reagent Recurrence Recurrent tumor Risk Reduction Small Interfering RNA T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Toxic effect Tumor Immunity Vaccinated Vaccination Vaccines antigen processing aptamer cancer therapy chronic infection clinical application clinically relevant combinatorial high risk invariant chain mortality neoantigen vaccination neoantigens neoplastic cell novel nucleolin patient subsets pre-clinical premalignant prevent programs prototype synergism tumor vaccination strategy

项目摘要

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.

针对大多数患者特异性新抗原的患者疫苗接种在以下方面提出了重大挑战