ANTIGEN SPECIFIC T CELL THERAPY FOR LEUKEMIA

恶性肿瘤复发仍然是患者失败的主要原因 接受异基因造血干细胞（HSC）移植， 急性和慢性白血病的治疗。供体T细胞特异性 受体次要组织相容性（H）抗原启动两种移植物， 抗宿主病（GVHD）和移植物抗白血病（GVL）反应， 有助于在同种异体HSC后完全消除白血病 移植供体外周血单核细胞（PBMC）输注 在许多移植后患者中诱导了完全缓解 复发，并证明了供体T细胞的抗白血病潜力 细胞，但这样的输注也引起了严重的GVHD。因此 利用T细胞疗法提高异基因造血干细胞移植成功率 移植需要鉴定效应细胞， 可以介导更有效和更有选择性的GVL效应。 的研究报告 申请人已经证明供体来源的CD 8+细胞毒性T细胞 (CTL)对组织限制性次要H抗原具有特异性的克隆可以 分离自HSC移植受者。这些CTL是细胞溶解性的， 白血病细胞，并将消除白血病祖细胞 在NOD/SCID小鼠中植入人AML所必需的。 的假设 在临床前和临床研究中， 从异基因HSC移植受者中分离T细胞 受体小H抗原特异性克隆和分子 造血干细胞选择性表达靶抗原的鉴定 细胞将允许特异性过继免疫疗法的发展， 增强GVL效应而不诱导GVHD。 具体目标是：1. 生成和表征CD 8+和CD 4 + 人次要组织相容性抗原特异性T细胞克隆 由造血细胞包括白血病母细胞表达。 2. 到 评价CD 8+和CD 4 + T细胞克隆的抗白血病疗效 特异于NOD/SCID小鼠中的次要组织相容性抗原 人类白血病模型。 3. 去识别编码组织的基因- CD 8 + T细胞识别的限制性次要组织相容性抗原 在患者或NOD/SCID中表现出抗白血病活性的克隆 小鼠 4. 评估AML移植后复发患者 过继免疫治疗的安全性和抗白血病作用 用HSV-TK修饰的T细胞克隆特异性地对次要组织相容性 受体造血细胞表达的抗原，但具有有限的或 在非造血组织中不表达。

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.