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: 6203042
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-08-24 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203042
• 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.

最近直接支持效应子贡献的证据 源自供体到抗白血病作用的细胞 骨髓移植已由包括我们的几个小组提供 拥有的，他们发现在接受CML的患者中 70％的未修饰或T细胞的接受者耗尽骨髓 可以重新引起移植后复发的同种异体移植物 通过输注进行处理，进入耐用的分子恢复 高剂量的供体衍生的外围血单元单元细胞 （PBMC）。 目前，白血病反应性细胞的性质（S） 在收养的PBMC中，降回恢复是未知的。 这种白血病选择性效应子可能包括反应性的T细胞 优先针对白血病特异性抗原或同种抗原 在白血病细胞上表达或反应针对白血病特异性 正如我们小组最近描述的那样，癌基融合产品 以及表现出hla-non限制的天然杀手细胞 细胞毒性活性。 该项目将重点放在开发上 收养细胞疗法和T细胞疗法的策略 生成体内（主动特异性免疫疗法）。合并 能够区分的选择或靶向效应细胞 白血病细胞。 人类白血病带有融合基因tragets 该项目将作为模型包括CML和PH+ ALL （P210和P190目标），AML-M2，T（8-21）（P92）和AML-M4，INV （16）（P67）。 目的是：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）在体外敏化和传播， 白血病相关融合基因肽特异性T淋巴细胞 并将这些细胞描述为它们的抗原特异性 它们的相对增殖和细胞毒性反应 与HLA匹配的肽相比 带有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T细胞和NK细胞相比 在继承转移到异种移植后，体外和体内 带有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“证明 原本“对于这种方法。这些结果 临床前研究将用于制定临床试验 评估接种供体的抗血症活性，或 患有CML，pH+全部或AML的患者携带融合基因产物。