POTENTIATION OF LEUKEMIA RESISTANCE CONFERRED BY MARROW ALLOGRAFT

同种异体骨髓移植增强白血病抵抗力

• 批准号: 6336336
• 负责人: DAVID A SCHEINBERG
• 金额: $ 24.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336336
• 关键词: MHC class I antigen; SCID mouse; T lymphocyte; acute lymphocytic leukemia; antibody specificity; antigen presentation; bone marrow transplantation; cell line; cell transplantation; cell type; chronic myelogenous leukemia; clinical research; electroporation; fusion gene; histocompatibility gene; human subject; leukemia; neoplasm /cancer immunology; oncogenes; peptides; transfection; transplantation immunology

Recently direct evidence supporting the contribution of effector cells derived from the donor to the anti-leukemic effects of a marrow graft has been provided by several groups including our own, who have found that among patients transplanted for CML over 70 percent of recipients of unmodified or T cell depleted marrow allografts who have relapsed post transplant can be reinduced into durable molecular remissions by treatment with infusions of high doses of donor-derived peripheral blood monounclear cells (PBMC). At present, the nature of the leukemia reactive cells(s) in adoptively transferred PBMC that incude remissions is unknown. Such leukemia-selective effectors may include T-cells reactive against leukemia-specific antigens or alloantigens preferentially expressed on leukemic cells or reactive against leukemia-specific oncogene fusion products, as recently described by our group, as well as natural killer cells exhibiting HLA-non-restricted cytotoxic activity. This project will focus on the development of strategies of adoptive cell therapy, and T cell therapy generated in vivo (active specific immunotherapy). incorporating selected or targeted effector cells that are able to distinguish leukemic cells. Human leukemias bearing fusion gene tragets that will serve as models in this project include CML and Ph+ ALL (p210 and p190 targets), AML-M2, t(8-21) (p92) and AML-M4, inv (16) (p67). The Aims are: 1) To develop effective strategies for generating and selecting potentially immunogenic leukemia fusion gene peptides. 2) To sensitize and propagate in vitro, leukemia associated fusion gene peptide-specific T lymphocytes and to characterize these cells as to their antigen-specificity and their relative proliferative and cytotoxic responses against HLA-matched peptide loaded normal targets in comparison with leukemic cells bearing the fusion gene. 3) To assess the leukemia-specific activity of fusion gene peptide-specific T cells, in comparison with alloreactive T cells and NK cells both in vitro and in vivo, after adoptive transfer into xenografted SCID mice bearing the targeted human leukemia or a normal hematopoietic cell graft. These experiments constitute a "proof- of-principle" for this approach. The results of these preclinical studies will be used to formulate clinical trials to assess the antileukemic activity of vaccinating donors, or patients with CML, PH+ALL or AMLs bearing fusion gene products.

最近有直接证据支持效应器的贡献 来自供体的细胞具有抗白血病作用 骨髓移植是由几个团体提供的，包括我们的 他们自己发现，在因 CML 接受移植的患者中 70% 的接受者接受未经修饰或 T 细胞耗尽的骨髓 移植后复发的同种异体移植物可以重新诱导 通过输注治疗进入持久的分子缓解 高剂量的供体来源的外周血单核细胞 （外周血单个核细胞）。 目前，白血病反应细胞的性质 过继转移的 PBMC 中是否出现缓解尚不清楚。 这种白血病选择性效应器可能包括反应性 T 细胞 优先针对白血病特异性抗原或同种异体抗原 在白血病细胞上表达或对白血病特异性有反应 癌基因融合产品，正如我们小组最近描述的那样， 以及表现出 HLA 非限制性的自然杀伤细胞 细胞毒活性。 该项目将重点发展 过继细胞疗法和 T 细胞疗法的策略 体内产生（主动特异性免疫疗法）。并入 选定或靶向的效应细胞能够区分 白血病细胞。 携带融合基因特征的人类白血病 将作为该项目模型的包括 CML 和 Ph+ ALL （p210 和 p190 目标）、AML-M2、t(8-21) (p92) 和 AML-M4、inv （16）（第 67 页）。 目标是： 1) 制定有效的策略 用于产生和选择潜在的免疫原性白血病 融合基因肽。 2) 体外致敏和繁殖， 白血病相关融合基因肽特异性T淋巴细胞 并表征这些细胞的抗原特异性 及其相对增殖和细胞毒性反应 HLA 匹配肽负载的正常靶标与 携带融合基因的白血病细胞。 3) 评估 融合基因肽特异性T的白血病特异性活性 细胞，与同种异体反应性 T 细胞和 NK 细胞相比 在体外和体内，过继转移到异种移植后 携带目标人类白血病或正常小鼠的 SCID 小鼠 造血细胞移植。 这些实验构成了“证据” 这种方法的原则”。这些结果 临床前研究将用于制定临床试验 评估疫苗接种捐赠者的抗白血病活性，或 携带融合基因产物的 CML、PH+ALL 或 AML 患者。