Combining repetitive element-specific T cells with epigenetic therapy to treat ovarian cancer

重复元件特异性 T 细胞与表观遗传疗法相结合治疗卵巢癌

基本信息

批准号：
10613918
负责人：
Erin Elizabeth Grundy
金额：
$ 4.22万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613918
关键词：
Antigen Presentation Pathway Antigen Targeting Antigens Bioinformatics Biological Assay Blood donor Cancer Model Cancer Patient Cancer cell line Cell Differentiation process Cells Coculture Techniques Color Competence Critical Thinking Data Development Elements Endogenous Retroviruses Epigenetic Process Epitopes Excision Experimental Designs Flow Cytometry Genes Genetic Materials Genetic Transcription Genomic Segment Genomics Goals HLA Antigens Histocompatibility Antigens Class I Human Immune Immune response Immune system Immunologics Immunophenotyping Immunosuppression Immunotherapy In Vitro Innate Immune Response Interferon Type II Interferons Knowledge Laboratories Lytic Malignant - descriptor Malignant neoplasm of ovary Mentors Normal tissue morphology Operative Surgical Procedures Patients Peptide Library Peptides Positioning Attribute Postdoctoral Fellow Predisposition Process Proteins Protocols documentation Publishing RNA Recurrent disease Repetitive Sequence Research Role Running Sampling Scientist Solid Neoplasm Source Specificity Surface Survival Rate T cell therapy T-Cell Activation T-Lymphocyte Testing Therapeutic Transcript Tumor Antigens Up-Regulation Viral Virus Whole Blood anti-tumor immune response bioinformatics tool cancer cell career cell killing chemotherapy clinically relevant curative treatments cytotoxicity epigenetic therapy experience experimental study immunodeficient mouse model immunogenic immunogenicity in vivo innovation mimicry mouse model neoplastic cell novel novel therapeutic intervention ovarian neoplasm prediction algorithm protein aminoacid sequence response skills success therapeutic target transcriptome sequencing treatment strategy tumor tumor immunology tumor microenvironment tumor-immune system interactions viral RNA

项目摘要

The five year survival rate for ovarian cancer (OC) patients has remained at 47% for over two decades. OC is characterized by a highly suppressive tumor microenvironment and current research efforts focus on reversing this immune suppression. One way to activate the immune response against OC is using epigenetic therapeutics, which stimulate an interferon response in cancer cells by inducing the transcription of repetitive elements (REs)—genomic regions that resemble the genetic material of some viruses. As REs are normally silent in terminally differentiated cells, their upregulation in tumor cells suggests that these genomic elements can be used as inducible treatment targets. T cells specific for an RE-derived antigen, the non-functional envelope gene of endogenous retrovirus K (ERV-K-Env), can recognize their cognate antigen and kill OC cells while sparing healthy cells. Whether these T cells will be more lytic when combined with immunogenic epigenetic therapy is unknown. Aside from ERV-K-Env, other epigenetically upregulated REs serve as an unexplored pool of tumor-associated antigens that may be novel treatment targets. I hypothesize that combining epigenetic therapy with RE-specific T cells will have potent immunogenic and targeted anti-tumor efficacy in OC. In Aim 1, I will determine the effect of combination epigenetic therapy and ERK-K-Env-specific T cells in OC. Preliminary data suggest this candidate RE, ERV-K-Env, is a targetable tumor-associated antigen in OC. I hypothesize that combining epigenetic therapy with ex vivo expanded ERV-K-Env-specific T cells will result in targeted immunogenic OC cell killing. ERV-K-Env-specific T cells will be expanded ex vivo from whole blood donors and assessed in vitro for antigen specificity. I will co-culture the expanded T cells with epigenetically treated OC cells and assess T cell activation and cytotoxicity in vitro and in vivo. In Aim 2, I will identify and target additional tumor-associated RE peptides as novel OC tumor antigens. Preliminary data from my lab suggest that epigenetic treatment results in the upregulation of REs and their presentation on the surface of OC cells to the immune system. I hypothesize that diverse tumor-associated REs upregulated by epigenetic therapy can be therapeutically relevant T cell targets in OC. Bioinformatic tools will be used to identify which REs upregulated by epigenetic therapy have the potential to be T cell antigens. I will validate the immunogenicity of these antigens by expanding RE-specific T cells from healthy donors and assess the clinical relevance of the experimentally validated REs as treatment targets using OC patient T cells. Completion of the proposed project will provide new knowledge on the combination of epigenetic therapy with RE-specific T cells as a novel immunogenic and potentially curative treatment strategy for OC. Collectively, these innovative interdisciplinary experiments will shed light on the understudied role of REs as therapeutic targets while further elucidating the mechanisms involved in activating an anti-tumor immune response that may be applicable to other solid tumors.

卵巢癌 (OC) 患者的五年生存率二十多年来一直保持在 47%。 OC 的特点是高度抑制的肿瘤微环境，目前的研究工作集中在逆转这种免疫抑制的一种方法是使用表观遗传来激活针对 OC 的免疫反应。疗法，通过诱导重复的转录来刺激癌细胞中的干扰素反应元素（RE）——与某些病毒的遗传物质相似的基因组区域。在终末分化细胞中沉默，它们在肿瘤细胞中的上调表明这些基因组元件可用作针对 RE 衍生抗原（非功能性抗原）的诱导性治疗靶标。内源性逆转录病毒K（ERV-K-Env）的包膜基因，可以识别其同源抗原并杀死OC细胞当与免疫原性表观遗传相结合时，这些 T 细胞是否会更具溶解性。除了 ERV-K-Env 之外，其他表观遗传上调的 RE 也是一个未开发的池。肿瘤相关抗原可能是新的治疗靶点。 RE 特异性 T 细胞治疗将在 OC 中具有有效的免疫原性和靶向抗肿瘤功效。在目标 1 中，我将确定表观遗传疗法和 ERK-K-Env 特异性 T 细胞联合治疗的效果 OC。初步数据表明，该候选 RE，ERV-K-Env，是 OC I 中的一种可靶向肿瘤相关抗原。很快，将表观遗传疗法与离体扩增的 ERV-K-Env 特异性 T 细胞相结合将导致靶向免疫原性 OC 细胞杀伤，ERV-K-Env 特异性 T 细胞将从体外扩增。我将与全血捐献者进行体外抗原特异性评估。表观遗传学处理的 OC 细胞并评估体外和体内 T 细胞活化和细胞毒性。在目标 2 中，我将鉴定并靶向其他肿瘤相关 RE 肽作为新的 OC 肿瘤抗原。我实验室的初步数据表明，表观遗传治疗会导致 RE 及其相关物质的上调。 OC细胞表面呈递给免疫系统。表观遗传疗法上调的 RE 可能是 OC 中治疗相关的 T 细胞靶点。工具将用于识别哪些 RE 通过表观遗传疗法上调，有可能成为 T 细胞抗原。我将通过扩展来自健康捐赠者的 RE 特异性 T 细胞来验证这些抗原的免疫原性，使用 OC 患者 T 细胞评估经实验验证的 RE 作为治疗目标的临床相关性。拟议项目的完成将为表观遗传疗法的结合提供新的知识 RE 特异性 T 细胞作为 OC 的一种新型免疫原性和潜在治愈性治疗策略。这些创新的跨学科实验将揭示 RE 作为治疗药物的作用。目标，同时进一步阐明激活抗肿瘤免疫反应所涉及的机制，这可能适用于其他实体瘤。