AUTOLOGOUS ANTI-CML IMMUNITY

自体抗 CML 免疫

• 批准号: 6332461
• 负责人: DAVID CLAXTON
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-12 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6332461
• 关键词: SCID mouse; apoptosis; autologous transplantation; cell mediated cytotoxicity; cellular immunity; chronic myelogenous leukemia; clinical research; clinical trial phase I; combination cancer therapy; cyclophosphamide; cytokine; cytotoxic T lymphocyte; dendritic cells; fluorescent in situ hybridization; helper T lymphocyte; hematopoietic stem cells; histocompatibility typing; human subject; human therapy evaluation; interleukin 2; mixed tissue /cell culture; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; passive immunization; polymerase chain reaction

There is abundant data documenting that patients with CML have residual normal hematopoietic stem cells able to repopulate the marrow and yield major cytogenetic remissions of the disease after cytotoxic or Interferon therapy. Up until now remissions following cytotoxic therapy or autologous transplants have unfortunately been relatively short lived. Recently we have demonstrated for the first time that CML derived, Ph1 positive dendritic cells may activate autologous lymphocytes to yield leukemia specific cytotoxic effector cells (DC/AL). We hypothesize that these DC/AL may be used for the generation for effective anti-CML therapy. Our objective in this project is thus to develop novel autologous cellular therapies which will produce long-term cytogenetic remissions of this disease. In order to do so we propose clinical studies of DC/AL infusion in late chronic phase CML. The novel information regarding the activity of DC/AL will also be pursued in the laboratory in order to better define the nature of the effector cell interaction with and cytolysis of the leukemic cells. Specifically we will: 1) Define the toxicity and anti-leukemic efficacy of CML-dendritic cell (DC) stimulated autologous lymphocytes in patients with late chronic phase CML. 2) Correlate in-vitro anti-leukemic cellular recognition and other characteristic and other characteristics of anti-CML effector cells generated by stimulation of autologous lymphocytes by CML-dendritic cells. Dr. Belmont's NOD-SCID mouse system of will be used to verify the activity of DC/AL for the CML stem cell. 4) Establish the mechanism of anti-CML activity of CML-dendritic cell stimulated lymphocytes. The relative roles of perforin, granzyme B and Fas mediated cell death will be explored. This program has the potential to yield curative therapies for patients with advanced CML lacking other treatment options.

有大量的数据记录，CML患者有残留 正常的造血干细胞能够再填充骨髓并产生 细胞毒性或干扰素后的主要细胞遗传学解散 治疗。到目前为止，细胞毒性疗法或自体后的缓解 不幸的是，移植相对较短。最近我们 首次证明了CML得出的PH1阳性 树突状细胞可能会激活自体淋巴细胞以产生白血病 特异性细胞毒性效应细胞（DC/AL）。我们假设这些DC/Al 可用于有效的抗CML治疗。我们的 因此，该项目的目标是发展新型的自体细胞 可以长期对此产生细胞遗传学的疗法 疾病。为此，我们提出了直流/Al输注的临床研究 在晚期慢性期CML中。有关活动的新颖信息 DC/Al也将在实验室中进行，以便更好地定义 效应细胞与白血病相互作用的性质 细胞。具体而言，我们将：1）定义毒性和抗白血病 CML树枝状细胞（DC）刺激自体淋巴细胞在 患有晚期CML晚期的患者。 2）与体外抗Leukemic相关 细胞识别以及其他特征和其他特征 通过刺激自体淋巴细胞产生的抗CML效应细胞 由CML树枝状细胞。 Belmont博士的点头鼠标鼠标系统将是 用于验证DC/Al对CML干细胞的活性。 4）建立 CML树突细胞的抗CML活性的机制刺激 淋巴细胞。穿孔蛋白，粒酶B和FAS介导的相对作用 细胞死亡将被探索。该计划有可能产生 缺乏其他治疗的晚期CML患者的治疗疗法 选项。