Programmable Off-the-Shelf Dendritic Cells as an Immunotherapy Discovery Platform

可编程现成树突状细胞作为免疫治疗发现平台

基本信息

批准号：
10449196
负责人：
David Minh Truong
金额：
$ 39.17万
依托单位：
NEW YORK UNIVERSITY
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449196
关键词：
Address Adoptive Immunotherapy Alleles Allogenic Antigen-Presenting Cells Antigens Autologous Award Base Pairing Basic Science Binding Cell Line Cell physiology Cells Clinic Communicable Diseases Complex Consumption Custom Cytotoxic T-Lymphocytes DNA Dendritic Cell Vaccine Dendritic Cells Endogenous Retroviruses Engineering Genes Genetic Genome Goals HLA Antigens Haplotypes Harvest Human Human Genome Immune Immune system Immunotherapy In Vitro Industrialization Investments Libraries Malignant Neoplasms Marshal Mature T-Lymphocyte Methods Modification National Institute of Allergy and Infectious Disease Patients Peptides Persons Population Positioning Attribute Procedures Proliferating Reporter Research Research Personnel Role Safety Solid Neoplasm Source Stress Stretching Surface System T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Time Training Transgenes Tumor Antigens Tumor-Infiltrating Lymphocytes Untranslated RNA Vaccines Validation Vision Work Writing cancer immunotherapy career chemotherapy chimeric antigen receptor combinatorial directed differentiation efficacy testing engineered T cells epigenetic silencing genome-wide high reward high risk induced pluripotent stem cell induced pluripotent stem cell technology innovation investigator training monocyte neoplastic cell new technology next generation sequencing novel therapeutics peripheral blood programs receptor refractory cancer synthetic biology technology development tumor

项目摘要

Project Summary Adoptive Cell Immunotherapy using patient harvested T cells engineered against tumor-specific targets has ushered in a new therapeutic era. However, the lack of tumor-specific targets and T cell receptors limits the addressable cancers. A promising approach for solid tumors uses T cell receptors (TCRs) directed against tumor- specific antigens (TSAs) displayed on HLA receptors found on the surface of nearly every cell. Unfortunately, HLAs are highly polymorphic genes between people. This restricts both the TCRs and TSAs to a small number of patients. A platform that expands the number of HLA-restricted TSAs and TCRs will transform the entire immunotherapy pipeline. Here, I propose to address this unmet need by generating programmable Dendritic cells (DCs) – professional antigen presenting cells that function to mature and activate naive T cells. Programmable DCs would permit the discovery of new TCRs, validation of TSAs, and perhaps be used as "living" vaccines to marshal a patient’s own immune system against infectious disease and cancer. Thus far, efforts to leverage the potential of DCs have been limited principally by: (1) an inability to produce cells with HLAs matched to patients;; (2) an inability to robustly test and validate new TSAs against TCRs;; and (3) an inability to produce "off-the-shelf" DCs at industrial scale. As a new innovator, my vision is to produce off-the-shelf Dendritic Cells pre-engineered to match any HLA haplotype (even rare ones) and pre-encoded with any combination of TSAs. Using this new platform, my group will search for and validate "universal" TSAs/TCRs that can be used broadly in TCR-Therapy for any patient. Specifically, we will focus on peptides expressed from regions of the genome normally epigenetically silenced, but re-activated in tumor cells (such as endogenous retroviruses). To reach this goal, we will continue development of technology enabling the "writing" of millions of base-pairs of DNA in human induced pluripotent stem cells (iPSCs). This technology allows direct customization of the large HLA locus of iPSCs in a single step;; introduction of libraries of potential TSAs;; and integration of synthetic reporter constructs (which are excisable for safety) for enhancing the in vitro directed differentiation of iPSCs to DCs. Thus, allogeneic programmed DCs will catalyze a wide variety of immunotherapy applications and expand access of these advanced treatments for a greater number of patients.

项目概要使用患者采集的针对肿瘤特异性靶标的 T 细胞进行过继细胞免疫疗法迎来了一个新的治疗时代，然而，肿瘤特异性靶点和T细胞受体的缺乏限制了它的发展。可寻址的癌症。治疗实体瘤的一种有前途的方法是使用针对肿瘤的 T 细胞受体 (TCR) 不幸的是，几乎每个细胞表面都存在 HLA 受体上的特异性抗原 (TSA)。 HLA 是人与人之间高度多态性的基因，这限制了 TCR 和 TSA 的数量。扩大 HLA 限制的 TSA 和 TCR 数量的平台将改变整个患者。免疫治疗管道。在这里，我建议通过生成可编程树突状细胞（DC）来解决这一未满足的需求 – 专业具有成熟和激活初始 T 细胞功能的抗原呈递细胞将允许发现新的 TCR、验证 TSA，并可能用作“活”疫苗来整理患者自己的疫苗因此，人们正在努力利用 DC 的潜力来对抗传染病和癌症。主要受到以下限制：(1) 无法产生与患者相匹配的 HLA 细胞；(2) 无法产生与患者相匹配的 HLA 细胞；根据 TCR 稳健地测试和验证新的 TSA；以及 (3) 无法在工业领域生产“现成的”DC 规模。作为一名新的创新者，我的愿景是生产现成的预设计树突状细胞，以匹配任何 HLA 单倍型（甚至是罕见的）并使用 TSA 的任何组合进行预编码。使用这个新平台，我的团队将寻找并验证可广泛用于任何患者 TCR 治疗的“通用”TSA/TCR。，我们将重点关注通常表观遗传沉默的基因组区域表达的肽，特别是但在肿瘤细胞中重新激活（例如内源性逆转录病毒），为了实现这一目标，我们将继续下去。技术的发展使得人类诱导多能性中数百万个 DNA 碱基对的“写入”成为可能干细胞 (iPSC)。该技术允许一步直接定制 iPSC 的大 HLA 基因座；；引入潜在 TSA 库；以及合成报告构建体的整合（可切除）为了安全起见），用于增强 iPSC 向 DC 的体外定向分化。因此，同种异体编程的 DC。将促进多种免疫疗法的应用，并扩大这些先进疗法的可及性更多的患者。