Th1Th2 and Tc1Tc2 T Cell Subsets in Transplantation Therapy

移植治疗中的 Th1Th2 和 Tc1Tc2 T 细胞亚群

• 批准号: 9154270
• 负责人: DANIEL FOWLER
• 金额: $ 73.48万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9154270
• 关键词: Acute Graft Versus Host Disease; Address; Allogenic; Allografting; Area; Bone Marrow Transplantation; Cancer Patient; Cell Therapy; Cells; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Data; Dose; Dysmyelopoietic Syndromes; Elderly; Engineering; Engraftment; Family; Graft Rejection; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematology; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune; Impairment; Individual; Infection; Infusion procedures; Laboratories; Lymph; Marrow; Mediating; Medical; Metastatic Renal Cell Cancer; Methodology; Methods; Modeling; Multiple Myeloma; Mus; New Jersey; Non-Hodgkin' s Lymphoma; Organ; Organ Transplantation; Patients; Pharmaceutical Preparations; Prior Chemotherapy; Protocols documentation; Reaction; Refractory; Research; Sirolimus; Site; Stem Cell Research; T-Lymphocyte; T-Lymphocyte Subsets; Th2 Cells; Time; Translating; Transplantation; United States National Institutes of Health; Universities; cancer site; cancer therapy; cell type; chemotherapy; design; graft vs host disease; immunoregulation; in vivo; leukemia/lymphoma; mouse model; novel strategies; prevent; programs; response

Allogeneic hematopoietic stem cell transplantation, often referred to as "bone marrow transplantation", represents a curative therapy for many individuals with leukemia, lymphoma, multiple myeloma, and myelodysplastic syndrome. However, the broadened application of transplantation therapy of these cancers is limited by two immune reactions that are mediated primarily by T cells, namely graft-versus-host disease (GVHD; T cell attack of donor cells against the patient) and graft rejection (or the host-versus-graft response; HVGR). GVHD is the main cause of lethality after transplantation. The HVGR results in the need to administer toxic doses of chemotherapy prior to transplanation, and thereby results in the current limitation of transplantation to individuals having a closely matched donor either from within the family or through the National Marrow Donor Program. Our laboratory focuses on new T cell graft engineering strategies designed to prevent GVHD and graft rejection. In murine models, we have shown that donor Th2 cells, which are generated ex vivo in the presence of the immune modulation drug rapamycin, can potently inhibit GVHD while preserving a component of the beneficial graft-versus-tumor (GVT) effect; furthermore, such Th2 cells effectively prevent the rejection of fully genetically mis-matched hematopoietic stem cells. We have made significant progress in translating these findings to the clinic. We have developed a method for generating human Th2 cells in rapamycin, and we have initiated a clinical trial investigating these cells in patients with refractory hematologic malignancy. Current data are consistent with our murine data, as recipients of Th2 cells grown in rapamycin have a low rate of acute GVHD; furthermore, administration of Th2 cells has allowed for a significant reduction in the amount of preparative chemotherapy required to achieve engraftment of the allograft. Such allogeneic Th2 cells are currently being evaluated on two clinical protocols. In the first protocol, NIH Clinical Center Protocol #04-C-0055, patients with refractory hematologic malignancy such as leukemia, lymphoma, and multiple myeloma are receiving a low-intensity transplant that is supplemented with donor Th2 cells; currently, approximately 125 patients have received therapy on this protocol. In the second protocol, NIH Clinical Center Protocol #08-C-0088, patients with refractory and metastatic renal cell carcinoma are receiving a low-intensity transplant that is supplemented with multiple infusions of donor Th2 cells. Of note, both of these protocols are being implemented in a multi-center manner, with Hackensack University in New Jersey serving as the multi-center site. Relevant cancer sites: Non-Hodgkins Lymphoma, Multiple Myeloma. Relevant Research Areas: Bone Marrow Transplantation, Organ Transplantation Research, Hematology/Lymph, Stem Cell Research, Clinical Research.

异基因造血干细胞移植，通常被称为“骨髓移植”，代表了许多患有白血病、淋巴瘤、多发性骨髓瘤和骨髓增生异常综合征的个体的治愈性疗法。然而，这些癌症的移植治疗的广泛应用受到主要由T细胞介导的两种免疫反应的限制，即移植物抗宿主病（GVHD;供体细胞对患者的T细胞攻击）和移植物排斥（或宿主抗移植物反应; HVGR）。GVHD是移植后致死的主要原因。HVGR导致在移植前需要施用毒性剂量的化疗，从而导致目前对具有来自家庭内或通过国家骨髓供体计划的密切匹配的供体的个体的移植的限制。我们的实验室专注于新的T细胞移植工程策略，旨在防止GVHD和移植排斥反应。在小鼠模型中，我们已经表明，供体Th 2细胞，这是在免疫调节药物雷帕霉素的存在下离体产生的，可以有效地抑制GVHD，同时保留一个有益的移植物抗肿瘤（GVT）效应的组成部分;此外，这样的Th 2细胞有效地防止排斥完全遗传不匹配的造血干细胞。我们在将这些发现转化为临床方面取得了重大进展。我们已经开发了一种在雷帕霉素中产生人Th 2细胞的方法，我们已经开始了一项临床试验，研究这些细胞在难治性恶性血液病患者中的作用。目前的数据与我们的小鼠数据一致，因为在雷帕霉素中生长的Th 2细胞的受体具有低的急性GVHD率;此外，Th 2细胞的施用使得实现同种异体移植物植入所需的制备性化疗的量显著减少。这种同种异体Th 2细胞目前正在两个临床方案中进行评估。在第一个方案，NIH临床中心方案#04-C-0055中，患有难治性血液恶性肿瘤如白血病、淋巴瘤和多发性骨髓瘤的患者正在接受补充有供体Th 2细胞的低强度移植;目前，大约125名患者接受了该方案的治疗。在第二个方案，NIH临床中心方案#08-C-0088中，患有难治性和转移性肾细胞癌的患者正在接受补充有供体Th 2细胞的多次输注的低强度移植。值得注意的是，这两个方案都是以多中心的方式实施的，新泽西的Hackensack大学作为多中心研究中心。相关癌症部位：非霍奇金淋巴瘤、多发性骨髓瘤。相关研究领域：骨髓移植、器官移植研究、血液学/淋巴学、干细胞研究、临床研究。