Immunology of CLL I--Acitive immunotherapy

CLL I 的免疫学--主动免疫治疗

• 批准号: 6477412
• 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: 2001
• 资助国家: 美国
• 起止时间: 2001-07-11 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6477412
• 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以被宿主 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，能够识别此类抗原的 T 细胞可能会变得无反应。针对这种疾病的常规和一些新型化疗可能会对无反应性 T 细胞产生不利影响，而无反应性 T 细胞可能能够对 CLL 相关抗原做出反应。 CLL细胞可以通过体外CD40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 AdCD154）将编码 CD40 配体（CD154）的基因引入 CLL 细胞的策略的开发。我们发现感染 AdCD154 的 CLL 细胞可以在体外诱导自体 T 细胞反应，从而产生针对未修饰的 CLL 细胞的细胞毒性 T 淋巴细胞 (CTL)。这是 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 AdCD154-CLL 细胞给患有中度或高风险疾病的患者的安全性。这项临床试验和初步体外研究的令人鼓舞的结果支持了这样的假设：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。为了剖析对假定的 CLL 相关抗原的自发和诱导细胞反应，我们有以下具体目标。 (1) 在诊断时以及使用 CLL 研究联盟 (CRC) 开发的疗法治疗前后，检查患者血液 T 细胞表达的 T 细胞受体 Vbeta 库。 (2) 评估类似时间点的血液 T 细胞的前体频率，这些前体频率可以在体外 CD3/CD28 结扎后精心设计对 AdCD154-CLL 或自体 CLL 细胞的干扰素-γ 反应。 (3) 在本提案的项目 1 中定义与 CLL 发病机制或进展有关的基因编码的肽，这些肽可以作为潜在的 LL 相关抗原。 (4) 在能够识别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) 开展一项涉及多次输注自体 AdCD154-CLL 细胞的 II 期 CRC 基因治疗试验。通过这些研究，我们鉴定了 CLL 相关抗原，并开发了针对该疾病的新型免疫疗法。