Immunology of CLL II adoptive immunotherapy

使用目前可用的治疗方法，慢性淋巴细胞白血病是无法治愈的。我们已经探索了大剂量治疗和自体或异基因干细胞移植(SCT)的使用。然而，由于大多数患者年龄较大，这些入路并不适合大多数CLL患者。因此，有必要对这种疾病采取新的治疗策略。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能让我们优化方法，在体外产生和扩大肿瘤特异性T细胞，用于过继免疫治疗。我们认为必须克服几个问题。在这种疾病中，T细胞功能存在缺陷，必须了解这些缺陷才能得到有效的纠正。肿瘤细胞存在缺陷，尤其是它们向T细胞呈递抗原的能力。我们的目标是开发方法来扩大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，毒性应该是最小的。为了实现这一目标，提出了五个目标。首先，研究慢性淋巴细胞性白血病T细胞免疫抑制或无能的机制。第二，检查参与诱导有效抗原提呈能力的CLL细胞中的信号事件。第三，开发和优化产生和扩增自体和同种异体肿瘤特异性T细胞的方法，以达到最小的疾病状态。第五，为了将这些观察结果转化为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研究了治疗对CLL和T细胞功能的影响。该项目与项目3高度互动，并依赖于临床、生物统计学和组织标本核心。

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.