Immunology of CLL adoptive immunotherapy

这一提议的中心假设是人类CLL相关或特异性抗原的存在。然而，由于肿瘤宿主的T细胞识别和效应器功能的缺陷和/或肿瘤细胞的低效或无效的抗原提呈，没有产生临床上显著的抗肿瘤T细胞对CLL的反应。这项建议的目的是试图开发更有效的，新的过继T细胞免疫疗法，以消除CLL患者中微小的残留白血病细胞。我们建议进行基础实验室实验、临床前研究和扩大规模，以及实现这一目标所需的临床试验。为此，我们有以下具体目标：(1)确定CLL患者T细胞被诱导成为免疫功能不全的机制；(2)检测CD40连接后诱导CLL细胞呈递抗原的必要和充分的信号事件；(3)开发和优化方法来产生和扩大自体T细胞，并进行过继免疫治疗的临床试验；(4)开发和优化方法来产生和扩大同种异体T细胞，用于同种异基因干细胞移植(SCT)后的过继免疫治疗；(5)确定自体或同种异体过继T细胞免疫治疗对微小疾病患者的影响，评估PCR作为替代终点、复发和生存。关于CLL细胞信号转导的发现可能与项目1和项目2中提出的研究相关。这个项目是高度互动的，依赖于项目3中提出的调查人员和研究。

The central hypothesis of this proposal is that human CLL associated or specific antigens exist. However, due to defects in T cell recognition and effector function in the tumor bearing host and/or inefficient or ineffective antigen presentation by the tumor cells, no clinically significant anti-tumor T cell response to CLL is generated. The objective of this proposal is to attempt to develop more effective, novel adoptive T cell immunotherapy to eradicate minimal residual leukemia cells in patients with CLL. We propose undertake basic laboratory experiments, pre-clinical studies and scale up, and clinical trials necessary to achieve this objective. For this, we have the following specific aims: (1) determine the mechanism whereby T cells in patients with CLL are induced to become immune- incompetent; (2) examine the signaling events that follow CD40-ligation necessary and sufficient to induce competent antigen presentation by CLL cells; (3) develop and optimize methodologies to generate and expand autologous T cells and to undertake clinical trials of adoptive immunotherapy; (4) develop and optimize methodologies to generate and expand allogeneic T cells for adoptive immunotherapy following allogeneic stem cell transplantation (SCT); (5) determine the impact of autologous or allogeneic adoptive T cell immunotherapy in patients with minimal disease assessing PCR as a surrogate endpoint, relapse, and survival. The findings on signaling in CLL cells will likely have relevance to studies proposed in Project 1 and Project 2. This project is highly interactive and dependent upon investigators and studies proposed in Project 3.