ANTIGEN SPECIFIC T CELL THERAPY FOR LEUKEMIA

白血病抗原特异性 T 细胞疗法

基本信息

批准号：
2730228
负责人：
Edus Houston Warren
金额：
$ 11.01万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-01 至 2000-06-30
项目状态：
已结题

项目摘要

Relapse of the malignancy remains a major cause of failure for patients who undergo allogeneic hematopoietic stem cell (HSC) transplantation for the treatment of acute and chronic leukemia. Donor T cells specific for recipient minor histocompatibility (H) antigens initiate both graft- versus-host-disease (GVHD) and graft-versus-leukemia (GVL) reactions and contribute to the complete elimination of leukemia after allogeneic HSC transplant. Infusions of donor peripheral blood mononuclear cells (PBMC) have induced complete remissions in many patients with posttransplant relapse and have demonstrated the antileukemic potential of donor T cells, but such infusions have also caused significant GVHD. Thus, the use of T cell therapy to improve the success rate of allogeneic HSC transplantation will require the identification of effector cells that can mediate a more potent and more selective GVL effect. Studies by the applicant have demonstrated that donor-derived CD8+ cytotoxic T cell (CTL) clones specific for tissue-restricted minor H antigens can be isolated from HSC transplant recipients. These CTL are cytolytic against leukemic cells in vitro, and will eliminate the leukemic progenitor cell necessary for engraftment of human AML in NOD/SCID mice. The hypothesis to be evaluated in this proposal in preclinical and clinical studies is that the isolation from allogeneic HSC transplant recipients of T cell clones specific for recipient minor H antigens and the molecular identification of target antigens selectively expressed in hematopoietic cells will permit the development of specific adoptive immunotherapy to enhance GVL effects without inducing GVHD. The specific aims are: 1. To generate and characterize CD8+ and CD4+ T cell clones specific for human minor histocompatibility antigens expressed by hematopoietic cells including leukemic blasts. 2. To evaluate the antileukemic efficacy of CD8+ and CD4+ T cell clones specific for minor histocompatibility antigens in the NOD/SCID mouse model of human leukemia. 3. To identify the genes encoding tissue- restricted minor histocompatibility antigens recognized by CD8+ T cell clones which exhibit antileukemic activity in patients or in NOD/SCID mice. 4. To evaluate in patients with posttransplant relapse of AML and ALL, the safety and antileukemic effects of adoptive immunotherapy with HSV-TK modified T cell clones specific for minor histocompatibility antigens expressed by recipient hematopoietic cells but with limited or absent expression on nonhematopoietic tissues.

恶性肿瘤的复发仍然是患者失败的主要原因谁接受同种异体造血干细胞（HSC）移植急性和慢性白血病的治疗。供体T细胞特有的受体小组织相容性（H）抗原引发了两个移植物与宿主 - 疾病（GVHD）和移植物 - 白血病（GVL）反应和同种异体HSC后完全消除白血病移植。供体外周血单核细胞的输注（PBMC）已诱发了许多移植后患者的完全缓解复发并证明了供体t的抗白血病潜力细胞，但这种输注也引起了显着的GVHD。因此，使用T细胞疗法提高同种异体HSC的成功率移植将需要鉴定效应细胞可以调节更有效，更具选择性的GVL效果。研究申请人证明了供体衍生的CD8+细胞毒性T细胞（CTL）针对组织限制的小型H抗原的克隆可以是从HSC移植受者中分离出来。这些CTL是细胞溶解的体外白血病细胞，将消除白血病祖细胞在点头/SCID小鼠中植入人AML所需的必要。假设在临床前和临床研究中的这一建议中要评估从T细胞的同种异体HSC移植受者中分离针对受体小型H抗原和分子特异的克隆在造血性中选择性表达靶抗原的鉴定细胞将允许开发特定的收养免疫疗法增强GVL效应而不诱导GVHD。具体目的是：1。生成和表征CD8+和CD4+ T细胞克隆针对人类小型组织兼容性抗原由造血细胞（包括白血病爆炸）表达。 2 评估CD8+和CD4+ T细胞克隆的抗白血病功效针对点数/SCID小鼠中的较小组织相容性抗原人类白血病的模型。 3。确定编码组织的基因 CD8+ T细胞识别的限制次要组织相容性抗原在患者或点头/SCID中表现出抗白血病活性的克隆老鼠。 4。评估移植后AML复发的患者所有这些，采用免疫疗法的安全性和抗白血病作用与HSV-TK修饰的T细胞克隆有关的针对较小的组织相容性由受体造血细胞表达的抗原，但有限或在非杂质组织上没有表达。