ANTIGEN SPECIFIC T CELL THERAPY FOR LEUKEMIA

恶性肿瘤的复发仍然是患者失败的主要原因 接受异基因造血干细胞移植的患者 急慢性白血病的治疗。供者T细胞特异性 受体次要组织相容性(H)抗原启动移植物- 抗宿主病(GVHD)和移植物抗白血病(GVL)反应和 促进异基因造血干细胞移植后白血病的完全消除 移植。供者外周血单核细胞(PBMC)输注 在许多移植后患者中诱导完全缓解 复发，并证明了供者T细胞的抗白血病潜力 但这种输血也会导致严重的移植物抗宿主病。因此， 应用T细胞治疗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， 可以调节更强大和更有选择性的GVL效应。研究由The 申请者证明供者来源的CD8细胞毒性T细胞 (CTL)针对组织限制性次要H抗原的克隆可以是 从造血干细胞移植受者身上分离出来的。这些CTL对细胞有杀伤作用 白血病细胞在体外，并将消灭白血病祖细胞 人急性髓系白血病在NOD/SCID小鼠体内植入所必需的。假说 在临床前和临床研究中对这项建议进行评估的是 异基因造血干细胞移植受者T细胞的分离 受体次要H抗原的特异性克隆及其分子 在造血系统中选择性表达的靶抗原的鉴定 细胞将允许开发特定的过继免疫疗法来 在不引起移植物抗宿主病的情况下增强GVL效应。 其具体目标是：1.产生CD8和CD4并对其进行鉴定 人类次要组织相容性抗原特异性T细胞克隆 由包括白血病母细胞在内的造血细胞表达。2.至 CD8和CD4T细胞克隆的抗白血病效果评价 NOD/SCID小鼠次要组织相容性抗原的特异性 人类白血病模型。3.识别编码组织的基因- CD8 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 老鼠。4.对急性髓细胞白血病移植后复发患者进行评估 总而言之，过继免疫疗法的安全性和抗白血病作用 用HSV-TK修饰的组织相容性较差的T细胞克隆 受体造血细胞表达的抗原，但具有有限的或 在非造血组织中无表达。

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.