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

• 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
• 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

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.

项目总结/摘要 造血干细胞移植（HSCT）已成为一种强大的治疗无数的疾病。 被诊断患有血液疾病（如白血病或再生障碍性贫血）并接受HSCT治疗的患者， 在这些病例中，HSCT是唯一的治愈选择。然而，捐助者 这些移植的受体通常不是HLA相同的，导致免疫反应， 受体的同种异体反应性记忆T细胞识别供体上的“非自身”抗原， 细胞诱导对供体细胞和组织耐受性的最常见方法是终身给药 存在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，而不需要 终身免疫抑制我们实现这一目标的方法是提出一种分裂的CAR T细胞系统， 现成的抗体接头分子，以特异性地消耗受体的记忆T细胞， 免疫系统的免疫功能，同时保留其他T细胞亚群，以维持强大的免疫系统。该系统具有 在不重新设计T细胞的情况下切换靶点的能力，以及对多种抗原的反应， 同种异体反应性T细胞和增强混合嵌合体和移植耐受的建立。如果 成功，这项研究项目的结果将证明使用CAR T细胞治疗的可行性。 免疫耐受的诱导，可应用于HSCT以外的许多自身免疫性疾病的治疗， 包括1型糖尿病、类风湿性关节炎、白癜风和多种源于 自身反应性T细胞功能障碍