Engineering CAR T Cells to Establish Stable Mixed Chimerism in Allogeneic Transplantation

改造 CAR T 细胞以在同种异体移植中建立稳定的混合嵌合状态

基本信息

批准号：
10537182
负责人：
Menna Yamany Siddiqui
金额：
$ 2.8万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
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：
2022-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10537182
关键词：
Adult Allogenic Antibodies Antigen Targeting Antigens Aplastic Anemia Apoptosis Autoimmune Diseases B-Lymphocytes Binding Bone Marrow Bone Marrow Cells Bone Marrow Transplantation Bone Tissue CAR T cell therapy CD19 gene CD8B1 gene Cell surface Cells Chimerism Complex Diagnosis Disease Effectiveness Engineering FDA approved Fluorescein-5-isothiocyanate Functional disorder Genetic Goals Graft Rejection Hematological Disease Hematopoietic Stem Cell Transplantation Homologous Transplantation Immune Immune Tolerance Immune response Immune system Immunologic Deficiency Syndromes Immunologic Memory Immunosuppression Immunosuppressive Agents In Vitro In complete remission Insulin-Dependent Diabetes Mellitus Leukocytes Life Logic Malignant - descriptor Mediating Memory Methods Modality Modeling Monitor Mus Neoadjuvant Therapy Opportunistic Infections Organ Transplantation Pathway interactions Patients Peptides Performance Peripheral Blood Mononuclear Cell Process Protocols documentation Receptor Signaling Regimen Research Research Project Grants Resistance Rheumatoid Arthritis Risk SELL gene Signal Transduction Surface Surface Antigens System T memory cell T-Cell Depletion T-Cell Immunologic Specificity T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Tissues Toxic effect Transplant Recipients Transplantation Transplantation Tolerance Vitiligo Work antibody conjugate autoreactive T cell base cell type chimeric antigen receptor chimeric antigen receptor T cells clinical application combinatorial design effectiveness evaluation engineered T cells experience extracellular human leukocyte antigen testing humanized mouse immunoengineering improved improved outcome in vivo innovation interest leukemia leukemia/lymphoma mouse model novel strategies preservation prevent response therapeutic target tool transplant model treatment response

项目摘要

Project Summary/Abstract Hematopoietic stem cell transplantation (HSCT) has become a powerful treatment for a myriad of disorders. Patients diagnosed with blood disorders such as leukemia or aplastic anemia that are treated with HSCT have seen highly improved outcomes, and in some of these cases HSCT is the only curative option. However, donors and recipients of these transplants are commonly not HLA identical, resulting in an immune response due to interactions between the recipient’s alloreactive memory T cells that recognize “non-self” antigens on the donor cells. The most common method of inducing tolerance to the donor cells and tissue is by lifelong administration of immunosuppressive drugs that come with the risk of opportunistic infections and toxicities. The overarching goal of this project is to develop the necessary genetic tools to restore immune tolerance without the need for life-long immunosuppression. Our approach to achieving this is to propose a split CAR T cell system that uses off-the-shelf antibody adapter molecules to specifically deplete the recipient’s memory T cells that are reactive against the donor, while preserving other T cell subsets to maintain a robust immune system. This system has the ability to switch targets without reengineering the T cells and respond to multiple antigens to target only alloreactive T-cells and enhance the establishment of mixed chimerism and transplantation tolerance. If successful, the findings of this research project will demonstrate the feasibility of using CAR T cell therapy for the induction of immune tolerance that can be applied beyond HSCT to the treatment of many autoimmune conditions including type 1 diabetes, rheumatoid arthritis, vitiligo and a myriad of disorders that originate from autoreactive T cell dysfunction.

项目摘要/摘要造血干细胞移植（HSCT）已成为多种疾病的强大治疗方法。被诊断为血液疾病的患者，例如白血病或用HSCT治疗的性贫血的患者请参阅高度改进的结果，在某些情况下，HSCT是唯一的治愈方法。但是，捐助者这些移植的接受者通常与HLA相同，从而导致免疫响应接收者的同种反应性记忆T细胞之间的相互作用，这些记忆T细胞在供体上识别“非自身”抗原细胞。诱导供体细胞和组织诱导耐受性的最常见方法是终生给药具有机会性感染和毒性风险的免疫抑制药物。总体该项目的目标是开发必要的遗传工具以恢复免疫耐受性而无需终身免疫抑制。我们实现这一目标的方法是提出一个使用的分裂汽车T细胞系统现成的抗体适配器分子，以专门定义受体的记忆T细胞反应性针对供体，同时保留其他T细胞子集以维持强大的免疫系统。该系统具有切换目标的能力而无需重新设计T细胞并响应多种抗原以仅靶向靶同种异体T细胞并增强混合嵌合和移植耐受性的建立。如果成功，该研究项目的发现将证明使用CAR T细胞疗法的可行性可以在HSCT以外应用于许多自身免疫的免疫耐受性的诱导包括1型糖尿病，类风湿关节炎，白癜风和无数疾病的疾病自动反应性T细胞功能障碍。