Immunology of CLL adoptive immunotherapy

CLL 过继免疫治疗的免疫学

• 批准号: 6259048
• 负责人: JOHN G. GRIBBEN
• 金额: $ 4.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6259048
• 关键词: CD40 molecule; T lymphocyte; autologous transplantation; biological signal transduction; cell transplantation; chronic lymphocytic leukemia; clinical research; human subject; human tissue; immunotherapy; pathologic process; polymerase chain reaction; stem cells

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.

该提案的中心假设是人类 CLL 相关或特定抗原的存在。 然而，由于荷瘤宿主中T细胞识别和效应器功能的缺陷和/或肿瘤细胞低效或无效的抗原呈递，没有产生针对CLL的临床显着的抗肿瘤T细胞应答。 该提案的目的是尝试开发更有效、新颖的过继性 T 细胞免疫疗法，以根除 CLL 患者的微小残留白血病细胞。 我们建议进行实现这一目标所需的基础实验室实验、临床前研究和扩大规模以及临床试验。 为此，我们有以下具体目标：（1）确定诱导CLL患者T细胞免疫功能低下的机制； (2) 检查 CD40 连接后的信号转导事件，这些信号转导事件是诱导 CLL 细胞进行有效抗原呈递所必需且充分的； (3) 开发和优化方法来生成和扩增自体T细胞并进行过继性免疫疗法的临床试验； (4) 开发和优化方法来生成和扩增同种异体 T 细胞，用于同种异体干细胞移植 (SCT) 后的过继免疫治疗； (5) 确定自体或同种异体过继性 T 细胞免疫疗法对轻微疾病患者的影响，以 PCR 为替代终点、复发和生存进行评估。 CLL 细胞信号传导的发现可能与项目 1 和项目 2 中提出的研究相关。该项目具有高度互动性，并且依赖于项目 3 中提出的研究人员和研究。