Synthetic immunoreceptor systems for combinatorial tumor antigen detection

用于组合肿瘤抗原检测的合成免疫受体系统

• 批准号: 8313533
• 负责人: Chia-Yung Wu
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313533
• 关键词: Adoptive Immunotherapy; Antibodies; Antigen Receptors; Antigen Targeting; Antigens; Apoptosis; Binding; Cancer Biology; Cancer Immunology Science; Cell physiology; Cell surface; Cells; Cellular Immunology; Cessation of life; Clinical; Clinical Trials; Collaborations; Cytotoxic T-Lymphocytes; Detection; Differentiation Antigens; Engineering; Evaluation; Goals; Immune; Immunology; Immunotherapy; Knowledge; Laboratories; Logic; Lymphocyte; Malignant Neoplasms; Mediating; Methods; Modeling; Molecular; Molecular Immunology; Monitor; NK cell receptor NKB1; Natural Killer Cells; Normal Cell; Normal tissue morphology; Pathway interactions; Patients; Pennsylvania; Property; Proteins; Receptor Signaling; Research; Safety; Signal Pathway; Signal Transduction; Specificity; Surface; System; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Tumor Antigens; Universities; Work; base; cancer cell; cancer immunotherapy; career; cell type; combinatorial; comparative; cytotoxic; cytotoxicity; design; extracellular; improved; insight; killings; mouse model; neoplastic cell; operation; pre-clinical; receptor; response; skills; synthetic biology; synthetic protein; tissue culture; tumor

DESCRIPTION (provided by applicant): In adoptive immunotherapy, immune cells isolated from patients can be engrafted with synthetic proteins that enable the cells to perform therapeutic functions, such as destroying tumor cells. One class of these proteins is the chimeric antigen receptors (CARs), which are fusions of extracellular single chain antibodies and intracellular signaling domains. The customizable antibody portion can bind to a specific antigen marker on a target cell surface. The modular intracellular signaling portion of the CAR then initiates a response in the immune cell. In cancer immunotherapy, CAR-mediated recognition and killing of cancer cells based on a single marker on the cancer cell has been shown to be clinically useful. However, recent studies also reveal a significant pitfall in safety: markers that are highly abundant on tumor cells can also be present at lower abundance on some normal cells. Unintentional killing of such normal cells by CAR-carrying immune cells has led to severe toxicity or even death of the patient. This project proposes to achieve the following goals: (1) Develop CAR systems that mediate immune cell functions based on combinations of markers instead of single markers. The intended result is that only cancer cells with a specific combination of surface markers will be killed by the immune cell. This proof-of-principle project is envisioned to generate valuable insights into the designs of more sophisticated CAR systems and to improve clinical utility of synthetic protein receptors in cell- based immunotherapy. (2) Compare the properties of the developed CAR systems in both T cells and Natural Killer cells, two major types of immune cells that are therapeutically useful in adoptive immunotherapy. Studies have shown that due to innate differences within the immune cells, a CAR can manifest different functional properties in different cell types. Characterizing CARs and CAR systems in different immune cell types is therefore important for enriching the current understanding of molecular and cellular immunology while defining the range of clinical utility of CARs. By pursuing the proposed research goals, I expect to gain expertise in bio-engineering, cancer biology and immunology. The acquired knowledge and skills will prepare me for an independent career in synthetic biology and cancer immunology. PUBLIC HEALTH RELEVANCE: In adoptive immunotherapy for cancer, a patient's own immune cells can be engrafted with synthetic proteins so that the cells are capable of destroying tumors in the patient. However recent clinical trials revealed a pitfall - insufficient discriminaton between cancer and normal cells in the body, leading to undesirable killing of normal cells by the immune cells and severe toxicity. The goal of this project is to design synthetic protein-based systems that will improve immune cells' recognition of cancer cells and to enrich the current understanding of molecular signaling mechanisms in immune cells.

描述（由申请人提供）：在过继免疫治疗中，从患者分离的免疫细胞可以植入合成蛋白，使细胞能够执行治疗功能，如破坏肿瘤细胞。这些蛋白质中的一类是嵌合抗原受体（汽车），其是细胞外单链抗体和细胞内信号传导结构域的融合体。可定制的抗体部分可以结合靶细胞表面上的特异性抗原标志物。CAR的模块化胞内信号传导部分然后在免疫细胞中启动应答。在癌症免疫治疗中，基于癌细胞上的单一标志物的CAR介导的癌细胞识别和杀伤已显示出临床上有用。然而，最近的研究也揭示了一个重大的安全隐患： 在肿瘤细胞上高度丰富的标记物也可以以较低的丰度存在于一些正常细胞上。携带CAR的免疫细胞对这些正常细胞的无意杀伤导致了患者的严重毒性甚至死亡。本项目拟实现以下目标 目标：（1）开发CAR系统，其基于标记物的组合而不是单一标记物介导免疫细胞功能。预期的结果是，只有具有特定表面标志物组合的癌细胞才会被免疫细胞杀死。该原理验证项目旨在对更复杂的CAR系统的设计产生有价值的见解，并提高合成蛋白受体在基于细胞的免疫治疗中的临床效用。(2)比较开发的CAR系统在T细胞和自然杀伤细胞中的特性，这两种主要类型的免疫细胞在过继免疫治疗中具有治疗作用。研究表明，由于免疫细胞内的先天差异，CAR可以在不同的细胞类型中表现出不同的功能特性。因此，表征不同免疫细胞类型中的汽车和CAR系统对于丰富目前对分子和细胞免疫学的理解，同时定义汽车的临床用途范围是重要的。通过追求拟议的研究目标，我希望获得生物工程，癌症生物学和免疫学方面的专业知识。所获得的知识和技能将为我在合成生物学和癌症免疫学方面的独立职业做好准备。 公共卫生关系：在癌症的过继免疫治疗中，患者自身的免疫细胞可以植入合成蛋白质，以便细胞能够摧毁患者的肿瘤。然而，最近的临床试验揭示了一个陷阱-体内癌症和正常细胞之间的区分不足，导致免疫细胞对正常细胞的不期望的杀伤和严重的毒性。该项目的目标是设计基于合成蛋白质的系统，以提高免疫细胞对癌细胞的识别能力，并丰富目前对免疫细胞分子信号传导机制的理解。