Adoptive Transfer of Donor Tregs Specific Against Host Alloantigens for Presentio

针对 Presentio 宿主同种抗原特异性的供体 Tregs 的过继转移

• 批准号: 8710334
• 负责人: CLAUDIO ANASETTI
• 金额: $ 49.81万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710334
• 关键词: Acute Graft Versus Host Disease; Address; Adoptive Immunotherapy; Adoptive Transfer; Adult; Alloantigen; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; BCL2 gene; Blood; CD8B1 gene; Cell Count; Clinical Research; Clinical Trials; Complication; Cytomegalovirus; Data; Dendritic Cells; Deuterium; Development; Donor person; Dose; Drug Combinations; Dysmyelopoietic Syndromes; Equilibrium; Excision; Frequencies; Goals; Graft Rejection; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; Homing; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Incidence; Interleukin-10; Interleukin-15; Interleukin-2; Investigation; Label; Life; Lymphoid; Lymphoid Tissue; Lymphoma; Malignant Neoplasms; Methotrexate; Minor Histocompatibility Antigens; Multiple Myeloma; Non-Malignant; Opportunistic Infections; Organ; Organ Transplantation; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Pre-Clinical Model; Prevention; Prophylactic treatment; Randomized; Reaction; Recovery; Regulation; Regulatory T-Lymphocyte; Relapse; Research; Risk; Rodent; Rodent Model; SELL gene; Safety; Severities; Siblings; Sirolimus; Stem cell transplant; Stem cells; T-Lymphocyte; Tacrolimus; Technology; Testing; Therapeutic; Transplant Recipients; Transplantation; Tube; Umbilical Cord Blood; Viral; WT1 gene; cancer cell; chemokine receptor; chronic graft versus host disease; clinical application; disorder prevention; graft vs host disease; improved; in vivo; leukemia; mortality; pathogen; prevent; prospective; public health relevance; receptor; reconstitution; response; tumor

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is the main cause of stem cell transplant-related mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Regulatory T cells prevent GVHD in preclinical models and early trials. Adoptive transfer of poly-specific Tregs exploits their natural suppressive functions and aims to alter the in vivo balance of T effectors and Tregs. However, this approach may also produce the same broad immunosuppressive effects that are caused by drugs. Experimental rodent models from our lab and others demonstrate that alloantigen-specific Tregs are more effective at preventing GVHD and improving survival than polyspecific Tregs. Our Long-Term Goal is to exploit Tregs to prevent GVHD in humans without suppressing desirable immune responses against infectious pathogens or malignant cells. Given their low frequency in human blood, several groups have explored ex-vivo Treg expansion for therapeutic application and these expanded Tregs retain suppressive activity. In contrast to polyspecific Tregs expanded non-selectively, antigen-specific Tregs produce selective suppression of allo-responses with no effect on third-party responses and facilitate alloantigen-specific tolerance after HSCT and organ grafting in. Before these results find clinical application, early clinical studies are required to address scientific and mechanistic questions and move the field forward. Our central hypothesis is that donor Tregs specific for host alloantigens presented by dendritic cells will prevent GVHD more effectively than current standard immune suppressive drugs, while preserving immunity to viral pathogens and cancer-associated antigens. The objective of this application is to conduct a first-in-human Phase I adoptive immunotherapy trial of allo-specific Tregs for GVHD prevention after HLA- identical sibling HSCT. Important to the potential application of Tregs to human HSCT, is the development of an immune suppressive platform containing rapamycin that selectively permits survival, expansion and suppressive function of Tregs while inhibiting other effector T cells. By trace-labeling the Tregs, we will also assess Treg repopulation and survival after adoptive transfer to allograft recipients.

描述（申请人提供）：移植物抗宿主病（GVHD）是异基因造血干细胞移植（HSCT）后干细胞移植相关死亡的主要原因。调节性 T 细胞在临床前模型和早期试验中可预防 GVHD。多特异性 Tregs 的过继转移利用其天然抑制功能，旨在改变 T 效应子和 Tregs 的体内平衡。然而，这种方法也可能产生与药物引起的相同广泛的免疫抑制作用。我们实验室和其他实验室的实验啮齿动物模型表明，同种异体抗原特异性 Tregs 比多特异性 Tregs 更能有效预防 GVHD 和提高存活率。我们的长期目标是利用 Tregs 来预防人类 GVHD，而不抑制针对感染性病原体或恶性细胞的所需免疫反应。鉴于 Treg 在人类血液中的频率较低，一些研究小组已经探索了离体 Treg 扩增的治疗应用，并且这些扩增的 Treg 保留了抑制活性。与非选择性扩增的多特异性 Tregs 相比，抗原特异性 Tregs 会选择性抑制同种异体反应，而不影响第三方反应，并促进 HSCT 和器官移植后的同种异体抗原特异性耐受。在这些结果应用于临床之前，需要进行早期临床研究来解决科学和机制问题并推动该领域向前发展。我们的中心假设是，对树突状细胞呈递的宿主同种异体抗原具有特异性的供体 Tregs 将比目前的标准免疫抑制药物更有效地预防 GVHD，同时保留对病毒病原体和癌症相关抗原的免疫力。本申请的目的是在 HLA 相同同胞 HSCT 后进行同种异体特异性 Tregs 预防 GVHD 的首次人体 I 期过继免疫治疗试验。对于 Tregs 在人类 HSCT 中的潜在应用而言，重要的是开发含有雷帕霉素的免疫抑制平台，该平台选择性地允许 Tregs 的存活、扩增和抑制功能，同时抑制其他效应 T 细胞。通过对 Tregs 进行跟踪标记，我们还将评估 Treg 细胞在过继转移至同种异体移植受体后的再增殖和存活率。