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：
10456230
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/10456230
关键词：
Ablation Antigen Targeting 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 Intervention Lead Lesion MHC Class I Genes Malignant Neoplasms Measurable Mediator of activation protein Methods Modality Modeling Mus Mutation Neoplasm Metastasis Nucleic Acids Oligonucleotides Pathology Pathway interactions Patients Peptides Predisposition Procedures Reagent Recurrence Risk Small Interfering RNA T cell response T-Lymphocyte T-Lymphocyte Epitopes Testing Time Toxic effect Tumor Immunity Vaccinated Vaccination Vaccines anti-tumor immune response antigen processing aptamer base 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 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.

患者对大多数患者特异性的新抗原的疫苗接种正在构成主要挑战哪种抗原靶向，仅限于在其肿瘤中表达新抗原的患者的一部分。我们在这里提议针对一组普通的预定义抗原制定广泛适用的铃木策略通过下调抗原加工途径的关键介体，可以在肿瘤细胞中实验诱导，点击，ERAAP和不变链（II）。 TAP或ERAAP的遗传消融导致了I类能够刺激T细胞反应并抑制TAP或ERAAP的生长的限制性垂体不足的肿瘤细胞，而不变链的下调（II）导致否则呈现隐性II类表位。针对TAP，ERAAP或II下调引起的疫苗接种抗原将构成针对具有新抗原的新抗原疫苗接种策略并发，反复和未来的肿瘤克服了针对突变的疫苗接种的主要局限性 - 产生的患者特异性新抗原。我们的研究支持提案，表明针对TAP下调引起的疫苗接种抗原，通过将siRNA靶向小鼠的居民直流，直接通过CPG寡核苷酸（CpG-）靶向小鼠。 Tap siRNA），比针对原型患者特异性突变产生的疫苗接种更有效新抗原，没有可测量的毒性，并抑制了并发和未来肿瘤的生长在发育中，Recirence和Promantimant疾病的模型也被下调肿瘤使用宽范围的核醇蛋白结合APATMER将Tap SiRNA靶向原位肿瘤细胞（NUCL-TAP） sirna）。该提案的目的是优化诱发的新抗原疫苗接种策略，以设置在临床试验中评估的阶段：（1）。开发最佳方法来诱导新抗原抑制抗原加工，TAP，ERAAP和II的关键介体。我们假设鉴于 CD4+和CD8+ T细胞免疫，TAP或ERAAP下调的协同作用，引起CD8+ T细胞响应与II下调相结合，即引起CD4+ T细胞反应将是最有效的组合。（2）评估与细胞靶向免疫增强方式的组合。我们将测试两种新型肿瘤和T细胞靶向策略，以将肿瘤感知到促炎性免疫反应，即将“冷”转换为“热”肿瘤病变，并促进肿瘤内积累驻留CD8+ T细胞（TRM）。（3）开发用于临床试验的铅化合物。确定最好的在课堂目标，TAP，ERAAP，II或组合，以刺激人类CD8+ T细胞反应的体外使用 CpG-siRNA处理的DC，该DC将识别用Nucl-SiRNA处理的肿瘤细胞，以诱导表现在肿瘤细胞上说抗原。