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."

“在同种异体骨髓的情况下 移植（AlloBMT），供体T细胞介导有益的 移植物与白血病（GVL）效应并防止骨髓排斥； 但是，供体T细胞还可以产生移植物抗宿主病 （GVHD）。我们已经确定了TC2的供体CD8+ T细胞 表型，由它们分泌II型细胞因子及其分泌而定义 靶细胞裂解的介导，主要通过穿孔蛋白途径为 能够介导GVL效果并防止骨髓排斥 GVHD有限。当前的努力正在评估这种使用 非毛囊同藻的鼠模型中的TC2细胞。在 此外，试验临床试验评估供体TC2细胞的作用 在人类Allobmt的环境中，正在开发。总体 这项工作的目标是改善 Allobmt，并将AlloBMT的应用扩展到那些 缺乏HLA匹配供体的患者。在自动环境中， T细胞也可能在介导抗白血病作用中发挥作用。 正在开发鼠模型来评估FAS的作用 T细胞介导的合成性GVL效应中的细胞溶解途径。在 此外，对CLL患者的研究正在评估差异作用 I型与II型细胞因子在FAS的CLL细胞利用率上 路径。这些鼠类和临床前的人类研究可能会提供 调节FAS途径的基础 白血病。此外，我们开发了清除的方法论 来自周围T细胞种群的CLL细胞。评估协议 这种自体T细胞是否可以改善免疫恢复 开发基于嘌呤模拟的化学疗法后。”