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."

“在同种异体骨髓移植中， 在同种异体骨髓移植（alloBMT）中，供体T细胞介导了有益的 移植物抗白血病（GVL）效应和防止骨髓排斥; 然而，供体T细胞也可产生移植物抗宿主病， （移植物抗宿主病）。我们已经鉴定了Tc 2的供体CD 8 + T细胞， 表型，由其II型细胞因子的分泌及其 主要通过穿孔素途径介导靶细胞裂解， 能够介导GVL效应并防止骨髓排斥的药物组合物 有限的GVHD。目前正在努力评估这种方法的使用情况。 非清髓性同种异体BMT小鼠模型中的Tc 2细胞。在 此外，评估供体Tc 2细胞的作用的初步临床试验 在人类alloBMT的背景下，正在开发。整体 本工作的目的是提高抗白血病的效果， alloBMT，并将alloBMT的应用扩展到那些 缺乏HLA匹配供体的患者。在自体情况下， 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 此外，在CLL患者中的研究正在评估 I型与II型细胞因子对CLL细胞Fas利用的影响 通路这些小鼠和临床前人类研究可能提供 调节Fas途径以治疗 白血病此外，我们还开发了清除 来自外周T细胞群的CLL细胞。评价方案 这种自体T细胞是否可以改善免疫恢复 基于嘌呤类似物的化学疗法正在开发中。"