POTENTIATION OF LEUKEMIA RESISTANCE CONFERRED BY MARROW ALLOGRAFT

最近的直接证据支持效应器的贡献 来源于供体的细胞的抗白血病作用 几个组织提供了骨髓移植，包括我们的 他们发现，在接受CML移植的患者中， 70%的未修饰或T细胞耗尽的骨髓接受者 移植后复发的同种异体移植物可以重新诱导 通过输注以下药物治疗， 高剂量供体来源的外周血单个核细胞 （PBMC）。 目前，白血病反应细胞的性质 在过继转移的PBMC中，包括缓解是未知的。 这种白血病选择性效应物可以包括T细胞反应性受体。 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 癌基因融合产物，正如我们小组最近所描述的， 以及表现出HLA非限制性 细胞毒活性 该项目将重点关注开发 过继性细胞治疗和T细胞治疗的策略 活性特异性免疫疗法（Active Specific Immunotherapy）。结合 选择的或靶向的效应细胞能够区分 白血病细胞 携带融合基因的人白血病的目标是， 将作为本项目的模型，包括CML和Ph+ ALL (p210和p190靶标）、AML-M2，t（8-21）（p92）和AML-M4，inv (16)（第67页）。 目标是：1）制定有效的战略 用于产生和选择潜在免疫原性白血病 融合基因肽 2)为了在体外致敏和繁殖， 白血病相关融合基因肽特异性T淋巴细胞 并对这些细胞的抗原特异性进行表征 以及它们相对增殖和细胞毒反应， HLA匹配的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细胞白血病特异性活性 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， 携带靶向人白血病或正常人白血病的SCID小鼠 造血细胞移植 这些实验构成了一个“证据- “原则”是指这种方法。 的结果予以 临床前研究将用于制定临床试验， 评估接种供体的抗白血病活性，或 CML、PH+ALL或携带融合基因产物的AML患者。

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.