Th1-Th2 and Tc1-Tc2 T Cell Subsets in Transplantation Therapy

移植治疗中的 Th1-Th2 和 Tc1-Tc2 T 细胞亚群

基本信息

批准号：
9344119
负责人：
DANIEL FOWLER
金额：
$ 73.61万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/9344119
关键词：
Acute Graft Versus Host Disease Address Allogenic Allografting Area Autologous Autologous Transplantation Bone Marrow Transplantation CD8B1 gene 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 Interferon-alpha Laboratories Lymph Marrow Mediating Medical Metastatic Renal Cell Cancer Methodology Methods Multiple Myeloma Mus New Jersey Non-Hodgkin&apos s Lymphoma Organ Organ Transplantation Patients Pharmaceutical Preparations Phase I Clinical Trials Phenotype Prior Chemotherapy Procedures Protocols documentation Reaction Recovery Refractory Refractory Disease Research Resistance Sirolimus Site Stem Cell Research Stem cell transplant T-Lymphocyte T-Lymphocyte Subsets Th2 Cells Time Translating Transplantation United States National Institutes of Health Universities cancer site cancer therapy cell type chemotherapy curative treatments cytokine design graft vs host disease immunoregulation in vivo leukemia/lymphoma mouse model novel strategies prevent programs response

项目摘要

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 140 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. These protocols are being implemented in a multi-center manner, with Hackensack University in New Jersey serving as the multi-center site. We are also evaluating rapamycin-resistant T cells in the autologous transplantation setting. In this case, both CD4 and CD8 T cells are manufactured in the presence of IFN-alpha to skew cells towards a Th1 cytokine phenotype. We have completed a phase I clinical trial of autologous Th1-type T-Rapa cells in the context of multiple myeloma therapy (infusion of T cells after recovery from an autologous stem cell transplant procedure). Currently, we are also evaluating autologous T-Rapa cells without use of stem cell transplant for the therapy of refractory diseases. Relevant cancer sites: Non-Hodgkins Lymphoma, Multiple Myeloma. Relevant Research Areas: Bone Marrow Transplantation, Organ Transplantation Research, Hematology/Lymph, Stem Cell Research, Clinical Research.

同种异体造血干细胞移植（通常称为“骨髓移植”）代表了许多白血病，淋巴瘤，多发性骨髓瘤和骨髓增生性症状综合征的治疗疗法。但是，这些癌症的移植疗法的扩展应用受到了两种免疫反应的限制，这些反应主要由T细胞介导，即移植物抗宿主病（GVHD；供体细胞对患者的T细胞的T细胞发作）和移植抑制（或宿主 - 移植响应； GVHD是移植后致死性的主要原因。 HVGR导致需要在移植之前服用有毒剂量的化学疗法，从而导致当前移植到来自家庭内部或国家骨髓供体计划的人的移植限制。我们的实验室专注于旨在防止GVHD和移植拒绝的新的T细胞移植工程策略。在鼠模型中，我们已经表明，在存在免疫调节药物雷帕霉素的情况下是在体内产生的供体Th2细胞，可以在保留有益的移植物肿瘤（GVT）效应的同时有效抑制GVHD。此外，这种TH2细胞有效地防止了完全遗传错误匹配的造血干细胞的排斥。我们在将这些发现转化为诊所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类Th2细胞的方法，并且我们开始了一项临床试验，研究了难治性血液学恶性肿瘤患者的这些细胞。当前数据与我们的鼠数据一致，因为雷帕霉素中生长的Th2细胞的受体的急性GVHD率较低。此外，TH2细胞的给药使得植入同种异体移植所需的制备化疗量显着减少。目前正在对两种临床方案进行评估，这种同种异体TH2细胞正在评估。在第一个方案中，NIH临床中心方案＃04-C-0055，患有难治性血液系统恶性肿瘤的患者（例如白血病，淋巴瘤和多发性骨髓瘤）接受了供体TH2细胞补充的低强度移植。目前，大约有140名患者已接受该方案的治疗。在第二个方案（NIH临床中心方案＃08-C-0088）中，难治性和转移性肾细胞癌患者正在接受低强度移植，并补充了供体TH2细胞多次输注的。这些协议正在以多中心方式实施，新泽西州的Hackensack University担任多中心站点。我们还在自体移植设置中评估抗雷帕霉素的T细胞。在这种情况下，CD4和CD8 T细胞均在IFN-Alpha存在下生产，以使细胞偏向Th1细胞因子表型。在多发性骨髓瘤治疗（从自体干细胞移植程序中恢复后输注T细胞）的背景下，我们已经完成了自体Th1型T-RAPA细胞的I期临床试验。目前，我们还在评估自体T-Rapa细胞，而无需使用干细胞移植来治疗难治性疾病。相关癌症部位：非霍奇金斯淋巴瘤，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，干细胞研究，临床研究。