Autologous and Allogeneic T Cell Strategies for the Treatment of Hematologic Mal

治疗血液病的自体和同种异体 T 细胞策略

• 批准号: 6433441
• 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/6433441
• 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, to reduce the morbidity and mortality associated with GVHD, 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.

在同种异体骨髓移植（allogeneic bone marrow transplantation, alloBMT）中，供体T细胞介导有益的移植物抗白血病（graft- anti -leukemia， GVL）效应并防止骨髓排斥反应；然而，供体T细胞也可以产生移植物抗宿主病（GVHD）。我们已经确定了Tc2表型的供体CD8+ T细胞，其分泌II型细胞因子并主要通过穿孔素途径介导靶细胞裂解，能够介导GVL效应并防止有限GVHD的骨髓排斥。目前正在评估这种Tc2细胞在非清髓性同种异体骨髓转移小鼠模型中的应用。此外，正在开展评估供体Tc2细胞在人类同种异体骨髓转移中的作用的初步临床试验。这项工作的总体目标是提高同种异体bmt的抗白血病作用，降低与GVHD相关的发病率和死亡率，并将同种异体bmt的应用扩展到缺乏hla匹配供体的患者。在自体环境中，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细胞溶解途径在T细胞介导的同源GVL效应中的作用。此外，CLL患者的研究正在评估I型和II型细胞因子对CLL细胞利用fas途径的差异作用。这些小鼠和临床前的人类研究可能为调节fas通路治疗白血病提供基础。此外，我们已经开发了从外周T细胞群中清除CLL细胞的方法。评估这些自体T细胞是否可以改善嘌呤类似物化疗后的免疫恢复的方案正在开发中。