POTENTIATION OF LEUKEMIA RESISTANCE CONFERRED BY MARROW ALLOGRAFT

最近的直接证据支持效应器的贡献 来源于供者的细胞对白血病的抗白血病作用 骨髓移植已经由几个组织提供，包括我们的 OWN，他们发现在接受CML移植的患者中 70%的未经修饰或T细胞耗尽的受者骨髓 移植后复发的同种异体移植可以重新诱导 通过输注阿司匹林治疗成持久的分子缓解 高剂量供者来源的外周血单核细胞 (PBMC)。目前，白血病反应性细胞的性质(S) 在通过采用方式转移的PBMC中，包括缓解的情况尚不清楚。 这种白血病选择性效应可能包括T细胞反应性 优先对抗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的反应 癌基因融合产品，正如我们小组最近描述的那样， 以及表现出人类白细胞抗原非限制性的自然杀伤细胞 细胞毒活性。这个项目将专注于开发 关于过继细胞治疗和T细胞治疗的策略 在体内产生(主动特异性免疫疗法)。合并 能够区分的选定或靶向效应细胞 白血病细胞。携带融合基因的人类白血病 将作为模型在这个项目中包括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)制定有效的战略 用于产生和选择潜在的免疫原性白血病 融合基因多肽。2)在体外敏化和繁殖， 白血病相关融合基因多肽特异性T淋巴细胞 并根据这些细胞的抗原特异性来表征这些细胞 以及它们相对的增殖和细胞毒性反应 负载正常靶点的HL A匹配多肽与 携带融合基因的白血病细胞。3)评估 融合基因多肽特异性T细胞的白血病特异性活性 细胞与同种异体反应性T细胞和NK细胞的比较 异种移植瘤体外和体内过继移植 携带靶向人类白血病或正常的SCID小鼠 造血细胞移植。这些实验构成了一个“证据-- 这一方法的原则。这些结果 临床前研究将用于制定临床试验，以 评估接种疫苗的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。

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.