Immunology of CLL I--Acitive immunotherapy

CLL I 的免疫学--主动免疫治疗

• 批准号: 6594417
• 负责人: Thomas J Kipps
• 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/6594417
• 关键词: CD40 molecule; T cell receptor; T lymphocyte; anergy; antigen presenting cell; autologous transplantation; cell line; chronic lymphocytic leukemia; clinical research; clinical trial phase I; cytotoxic T lymphocyte; gene therapy; human subject; human therapy evaluation; human tissue; immunoconjugates; interferon gamma; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; stem cell transplantation; tumor antigens

The central hypothesis of this proposal is that there are chronic lymphocytic leukemia (CLL) associated antigens that can be recognized by host T cells. However, due to the CLL phenotype the T cells that can recognize such antigens may be rendered anergic. Conventional and some novel forms of chemotherapy for this disease may adversely affect anergic T cell that may be capable of responding to CLL-associated antigens. CLL cells can be converted into effective antigen presenting cells via CD40-ligation in vitro. This led to development of strategies for introducing the gene encoding the CD40-ligand (CD154) into CLL cells using recombinant adenovirus vectors, designated AdCD154. We find that CLL cells infected with AdCD154 can induce autologous T cell responses in vitro, leading to generation of cytotoxic T lymphocytes (CTL) against non-modified CLL cells. This served as the basis for a phase I gene therapy trial intended to examine the safety of a single intravenous infusion of autologous AdCD154-CLL cells to patients with intermediate or high-risk disease. The encouraging results from this clinical trial and preliminary in vitro studies support the hypothesis that there are CLL-associated antigens that can be recognized to host T cells and potentially targeted by host CTL, leading to immune clearance of CLL cells. To dissect the spontaneous and induced cellular responses to putative CLL-associated antigens we have the following specific aims. (1) Examine the expressed T cell receptor Vbeta repertoires of blood T cells of patients at diagnosis and pre- and post treatment with therapies developed by the CLL Research Consortium (CRC). (2) Evaluate the precursor frequency of blood T cells at similar time-points that can elaborate interferon-gamma in response to AdCD154-CLL or to autologous CLL cells after CD3/CD28-ligation in vitro. (3) Define peptides encoded by genes implicated in the pathogenesis or progression of CLL by in Project 1 of this proposal that could serve as potential LL- associated antigens. (4) Use T cell lines reactive with autologous CLL cells in strategies that can identify and isolate genes encoding tumor- associated antigens. (5) Develop a phase II CRC trial of gene therapy involving multiple infusion of autologous AdCD154-CLL cells. Through these studies we identify CLL-associated antigens and develop novel forms of immune-based therapies for this disease.

该提议的中心假设是存在可被宿主T细胞识别的慢性淋巴细胞白血病（CLL）相关抗原。然而，由于CLL表型，可以识别这些抗原的T细胞可能变得无反应性。传统的和一些新的形式的化疗对这种疾病可能会产生不利影响无能的T细胞，可能能够响应CLL相关抗原。CLL细胞可以通过体外CD 40连接转化为有效的抗原呈递细胞。这导致了使用重组腺病毒载体（称为AdCD 154）将编码CD 40-配体（CD 154）的基因引入CLL细胞的策略的发展。我们发现AdCD 154感染的CLL细胞在体外可以诱导自体T细胞反应，导致产生针对未修饰的CLL细胞的细胞毒性T淋巴细胞（CTL）。这成为I期基因治疗试验的基础，该试验旨在检查单次静脉输注自体AdCD 154-CLL细胞给中危或高危疾病患者的安全性。来自该临床试验和初步体外研究的令人鼓舞的结果支持以下假设：存在可以被宿主T细胞识别并可能被宿主CTL靶向的CLL相关抗原，从而导致CLL细胞的免疫清除。为了剖析对推定的CLL相关抗原的自发和诱导的细胞应答，我们具有以下具体目标。(1)在诊断时以及用CLL研究联盟（CRC）开发的疗法治疗前后检查患者血液T细胞的表达的T细胞受体Vbeta库。(2)评价在相似时间点血液T细胞的前体频率，其可以阐述干扰素-γ对体外CD 3/CD 28连接后的AdCD 154-CLL或自体CLL细胞的应答。(3)在本提案的项目1中定义由参与CLL发病机制或进展的基因编码的肽，其可以作为潜在的LL相关抗原。(4)在可以鉴定和分离编码肿瘤相关抗原的基因的策略中使用与自体CLL细胞反应的T细胞系。(5)开展一项涉及自体AdCD 154-CLL细胞多次输注的基因治疗II期CRC试验。通过这些研究，我们确定了CLL相关抗原，并开发了针对这种疾病的新型免疫疗法。