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Enhancing Treg Therapeutic Efficacy in GVHD with CARs

利用 CAR 增强 GVHD 中 Treg 的治疗功效

基本信息

批准号：
10684897
负责人：
Sara Bolivar Wagers
金额：
$ 2.79万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2021-09-13 至 2024-07-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684897
关键词：
Adoptive Transfer African American Alleles Allogenic Antigen Presentation Antigen-Presenting Cells Antigens Antitumor Response Autoimmune B lymphoid malignancy B-Cell Lymphomas B-Lymphocytes Blood Bone Marrow CD19 gene CD28 gene Cells Cellular biology Clinical Research Cyclophosphamide Cytolysis Cytotoxic T-Lymphocytes Data Disease Disparate Dose FDA approved Fluorescence Frequencies Genome engineering Goals Graft Rejection Granzyme HLA-A2 Antigen Hematologic Neoplasms Hematological Disease Hematopoietic Stem Cell Transplantation Hispanic Human Immune Immune response Immunosuppression Immunotherapy In Vitro Infection Inflammatory Infusion procedures Knock-out Knockout Mice Laboratories Left Leukemic Cell Lymphoma cell Malignant - descriptor Malignant Neoplasms Measures Mediating Modeling Morbidity - disease rate Mus Non-Malignant Organ Organ Transplantation Outcome Patient-Focused Outcomes Patients Pediatric Oncologist Phase Physicians Predisposition Prevention Production Property Receptor Signaling Recurrent tumor Regulatory T-Lymphocyte Reporter Reproducibility Research Proposals Scientist Second Primary Cancers Severity of illness Solid T cell therapy T-Cell Activation T-Cell Depletion T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenes Transplant Recipients Transplantation Transplantation Immunology Treatment Efficacy Tumor Antigens bioluminescence imaging bone marrow failure syndrome cell killing chimeric antigen receptor chimeric antigen receptor T cells clinical translation comparison control curative treatments cytokine cytokine release syndrome design disorder prevention graft versus host disease induction graft vs host disease graft vs leukemia effect high risk human imaging improved in vivo infection risk mortality mouse model novel novel strategies novel therapeutics perforin preclinical study prevent prophylactic rat orphan nuclear receptor NR4A1 response secondary lymphoid organ side effect skills transplant model

项目摘要

1 Project Summary/Abstract 2 3 Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematological disorders 4 but its efficacy is limited by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality after 5 HSCT. With current prophylactic measures 20-70% of HSCT patients develop GVHD and are left susceptible to 6 infection, tumor recurrence, and secondary malignancies. Pre-clinical and clinical studies show adoptive transfer 7 of regulatory T cells (Treg) is highly effective at preventing GVHD. Clinical translation has been hindered by low 8 Treg frequency in the blood, variable suppressive capacity of polyclonal Tregs, and the need to infuse high doses 9 to reproducibly suppress disease. Antigen-specific Tregs have been shown to be more potent than polyclonal 10 Tregs in autoimmune models and in solid organ transplants where HLA-A2 specific Tregs are given to suppress 11 responses against HLA-A2 disparate grafts. While this approach targets one of the most commonly mismatched 12 antigens, HLA-A2 is present in only 20% of African American and 34% of Hispanic patients. To overcome these 13 limitations, I will use chimeric antigen receptors (CAR) to redirect Tregs towards human CD19 (hCD19) B cells 14 using an FDA approved construct containing the 4-1BB co-stimulatory domain (CAR19). Unexpectedly, my 15 preliminary data with CAR19 Tregs demonstrate dual and opposing properties of GVHD suppression and killing 16 of leukemia cells including graft-versus-leukemia (GVL). Thus, my goal is to use Tregs specific for hCD19 present 17 on malignant B cells to mediate GVL and on non-malignant B cells to deplete these host antigen presenting cells 18 during the critical GVHD induction phase. I will use a murine major MHC mismatch model where recipient mice 19 express hCD19 on B cells. My preliminary studies demonstrate CAR19 Tregs improve GHVD survival and cause 20 hCD19 B cell depletion early after HSCT. We also found CAR19 Tregs mediate targeted killing of hCD19 21 lymphoma cells in vitro and maintained GVL in vivo unlike control Tregs. Understanding how CAR19 Tregs utilize 22 cytolysis for GVL while suppressing GVHD will help expand our understanding of CAR Treg biology and design 23 to maximize their use in allo-HSCT. I hypothesize CAR19 Tregs are bifunctional in their ability to suppress 24 excessive and deleterious immune responses (GVHD, CRS) and concurrently induce GVL effects. The findings 25 from this research proposal will elucidate the mechanisms by which CAR19 Tregs confer higher protection than 26 control Tregs or even CAR19 T cells at ameliorating GVHD, preventing cytokine release syndrome (CRS), and 27 uniquely promoting anti-tumor responses. The novel approach of redirecting CAR Tregs to tumor antigens opens 28 a new therapeutic avenue to prevent GVHD and improve allo-HSCT outcomes.

1项目概要/摘要 2 3异基因造血干细胞移植（HSCT）是许多血液系统疾病的治疗选择 4，但其疗效受到移植物抗宿主病（GVHD）的限制，GVHD是移植后发病率和死亡率的主要原因。 5例HSCT。在目前的预防措施下，20-70%的HSCT患者发生GVHD，并且容易发生GVHD。 6感染、肿瘤复发和继发恶性肿瘤。临床前和临床研究表明， 7的调节性T细胞（Treg）在预防GVHD方面非常有效。临床翻译受到低图8血液中Treg的频率、多克隆Treg的可变抑制能力以及需要输注高剂量 9、预防疾病。抗原特异性Tcl 4已被证明比多克隆Tcl 4更有效。 10自体免疫模型和实体器官移植中的TCLs，其中给予HLA-A2特异性TCLs以抑制 11例对HLA-A2不同移植物的反应。虽然这种方法针对的是最常见的不匹配之一， HLA-A2仅存在于20%的非洲裔美国人和34%的西班牙裔患者中。克服这些 13限制，我将使用嵌合抗原受体（CAR）重定向Tclase对人类CD 19（hCD 19）B细胞 14使用FDA批准的含有4-1BB共刺激结构域（CAR 19）的构建体。没想到，我的 15 CAR 19 T细胞的初步数据证明了GVHD抑制和杀伤的双重和相反性质 16例白血病细胞，包括移植物抗白血病（GVL）。因此，我的目标是使用特异性针对hCD 19存在的Tclase， 17对恶性B细胞介导GVL，对非恶性B细胞消耗这些宿主抗原呈递细胞 18在关键的GVHD诱导阶段。我将使用小鼠主要MHC错配模型， 19在B细胞上表达hCD 19。我的初步研究表明，CAR 19 THBE可以改善GHVD的生存率， 20例HSCT后早期hCD 19 B细胞耗竭。我们还发现CAR 19 T细胞介导hCD 19的靶向杀伤， 21淋巴瘤细胞，并在体内维持GVL，而不像对照组TCLs。了解CAR 19 TTRO如何利用 GVL的细胞溶解同时抑制GVHD将有助于扩大我们对CAR Treg生物学和设计的理解 23，以最大限度地发挥其在allo-HSCT中的作用。我假设CAR 19 T细胞在其抑制CAR 19 T细胞的能力方面是双功能的。 24过度和有害的免疫反应（GVHD，CRS），并同时诱导GVL效应。这些发现 25从这项研究提案将阐明的机制，CAR 19 T细胞赋予更高的保护比 26个对照TcR或甚至CAR 19 T细胞在改善GVHD、预防细胞因子释放综合征（CRS）方面的作用，以及 27独特地促进抗肿瘤反应。将CAR T重定向到肿瘤抗原的新方法 28预防GVHD和改善allo-HSCT结果的新治疗途径。