Immunology of CLL II adoptive immunotherapy

CLL II 过继免疫疗法的免疫学

• 批准号: 6594418
• 负责人: JOHN G. GRIBBEN
• 金额: $ 16.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-31 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594418
• 关键词: CD40 molecule; T lymphocyte; autologous transplantation; blood treatment; chronic lymphocytic leukemia; clinical research; human subject; immune tolerance /unresponsiveness; laboratory mouse; monoclonal antibody; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; pathologic process; stem cell transplantation

Chronic lymphocytic leukemia is incurable using currently available therapy. We have explored the use of high dose therapy and either autologous or allogeneic stem cell transplantation (SCT). However, since most patients are elderly age, these approaches are not suitable for the majority of patients with CLL. There is therefore a need for novel treatment strategies in this disease. The central goal of Project 4 is to study the mechanisms whereby there is no efficient T cell mediated immune response against the leukemic cells in this disease. Understanding of the mechanisms whereby this tumor evades immune recognition should allow us to optimize methodologies to generate and expand tumor specific T cells ex vivo for adoptive immunotherapy. We believe that several problems have to be overcome. In this disease there are defects in T cell function that have to be understood before they can be corrected effectively. There are defects in the tumor cells and in particular in their capacity to present antigens to T cells. We aim to develop methodologies to expand autologous and allogeneic tumor specific T cells and translate these findings into clinical trials examining the role of autologous and allogeneic T cell tumor specific immunotherapy to develop novel treatment strategies that if successful should have minimal toxicity. To achieve this goal, Five Aims are proposed. First, to study the mechanism of T cell immunosuppression or anergy in CLL. Second, to examine signaling events in the CLL cells involved in induction of efficient antigen presenting capacity . Third, to develop and optimize methods to generate and expand autologous and allogeneic tumor specific T cells for minimal disease state. Fifth, to translate these observations to clinical trials of tumor specific immunotherapy in potential tumor antigens, Projects 2, 5 and 6 to study the impact of therapy on CLL and T cell function. This project is highly interactive with Project 3, and is dependent upon the Clinical, Biostatistical and Tissue Specimen Cores.

使用目前可用的疗法无法治愈慢性淋巴细胞白血病。我们探索了高剂量疗法以及自体或同种异体干细胞移植（SCT）的使用。然而，由于大多数患者年龄较大，这些方法并不适合大多数 CLL 患者。因此，这种疾病需要新的治疗策略。项目 4 的中心目标是研究在这种疾病中没有有效的 T 细胞介导的针对白血病细胞的免疫反应的机制。了解这种肿瘤逃避免疫识别的机制应该使我们能够优化方法，在体外生成和扩增肿瘤特异性 T 细胞，用于过继性免疫治疗。我们认为必须克服几个问题。在这种疾病中，必须先了解 T 细胞功能缺陷，然后才能有效纠正。肿瘤细胞存在缺陷，特别是向 T 细胞呈递抗原的能力。我们的目标是开发方法来扩展自体和同种异体肿瘤特异性 T 细胞，并将这些发现转化为临床试验，检查自体和同种异体 T 细胞肿瘤特异性免疫疗法的作用，以开发新的治疗策略，如果成功，毒性应最小。为实现这一目标，提出了五个目标。首先，研究CLL中T细胞免疫抑制或无反应的机制。其次，检查 CLL 细胞中参与诱导有效抗原呈递能力的信号传导事件。第三，开发和优化方法来生成和扩增自体和同种异体肿瘤特异性 T 细胞，以实现最小的疾病状态。第五，将这些观察结果转化为针对潜在肿瘤抗原的肿瘤特异性免疫治疗的临床试验，项目2、5和6研究治疗对CLL和T细胞功能的影响。该项目与项目 3 高度互动，并且依赖于临床、生物统计和组织样本核心。