AUTOLOGOUS AND ALLOGENEIC T CELL STRATEGIES FOR HEMA C MALIGNANCY

HEMA C 恶性肿瘤的自体和同种异体 T 细胞策略

• 批准号: 6123770
• 负责人: DANIEL FOWLER
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6123770
• 关键词: autologous transplantation; bone marrow purging; bone marrow transplantation; chronic lymphocytic leukemia; cytokine; cytolysis; cytotoxic T lymphocyte; disease /disorder model; graft versus host disease; histocompatibility; homologous transplantation; laboratory mouse; transplant rejection; transplantation immunology

"In the setting of allogeneic bone marrow transplantation (alloBMT), donor T cells mediate a beneficial graft-versus-leukemia (GVL) effect and prevent marrow rejection; however, donor T cells can also generate graft-versus-host disease (GVHD). We have identified that donor CD8+ T cells of Tc2 phenotype, defined by their secretion of type II cytokines and their mediation of target cell lysis primarily via the perforin pathway, are capable of mediating a GVL effect and preventing marrow rejection with limited GVHD. Current efforts are evaluating the use of such Tc2 cells in murine models of non-myeloablative alloBMT. In addition, pilot clinical trials evaluating the effect of donor Tc2 cells in the setting of human alloBMT are being developed. The overall goal of this work is to improve the anti-leukemic effects of alloBMT, and to extend the application of alloBMT to those patients lacking an HLA-matched donor. In the autologous setting, T cells may also play a role in mediating anti-leukemic effects. Murine models are being developed to evaluate the role of the fas cytolytic pathway in T cell-mediated syngeneic GVL effects. In addition, studies in CLL patients are evaluating the differential role of type I versus type II cytokines on CLL cell utilization of the fas pathway. These murine and pre-clinical human studies may provide a basis for modulation of the fas pathway for the treatment of leukemia. In addition, we have developed methodologies to purge CLL cells from peripheral T cell populations. Protocols to evaluate whether such autologous T cells might improve immune recovery after purine analog-based chemotherapy are being developed."

“在异基因骨髓的背景下 移植(AllBMT)，供者T细胞介导的一种有益的 移植物抗白血病(GVL)效应和预防骨髓排斥反应； 然而，捐赠者的T细胞也会引发移植物抗宿主病 (GVHD)。我们已经鉴定出供者Tc2的CD8+T细胞 表型，由他们分泌的II型细胞因子和他们的 主要通过穿孔素途径介导靶细胞裂解，是 能够调节GVL效应并防止骨髓排斥的 只有有限的GVHD。目前的努力正在评估这种方法的使用 非清髓性异基因骨髓移植小鼠模型中的Tc2细胞。在……里面 此外，评估捐赠者Tc2细胞效果的先导性临床试验 在人类的背景下，异基因骨髓移植正在开发中。整体而言 这项工作的目的是提高抗白血病作用。 ，并将allBMT的应用范围扩展到 缺乏人类白细胞抗原相合供者的患者。在自体设置中， T细胞也可能在介导抗白血病作用中发挥作用。 正在开发小鼠模型来评估Fas的作用 T细胞介导的同基因GVL效应中的细胞溶解途径。在……里面 此外，对慢性淋巴细胞性白血病患者的研究正在评估这种不同的作用 I型与II型细胞因子对外周血淋巴细胞利用率的影响 路径。这些小鼠和临床前的人类研究可能提供 调控Fas通路治疗骨肉瘤的基础 白血病。此外，我们还开发了清除 外周T细胞群中的CLL细胞。用于评估的方案 这种自体T细胞是否可能促进免疫恢复 之后，以嘌呤类似物为基础的化疗正在开发中。