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有慢性淋巴细胞性白血病（CLL）相关的抗原可以被宿主T细胞识别。但是，由于CLL表型，可以识别此类抗原的T细胞可能会引起厌食症。常规和一些新型的对该疾病的化学疗法可能会对能够对CLL相关抗原做出反应的厌食T细胞产生不利影响。 CLL细胞可以通过CD40-Rigation在体外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（指定为ADCD154）引入编码CD40-配置基因（CD154）基因的策略。我们发现感染了ADCD154的CLL细胞可以在体外诱导自体T细胞反应，从而导致对非修饰CLL细胞的细胞毒性T淋巴细胞（CTL）产生。这是I期基因治疗试验的基础，该试验旨在检查自体ADCD154-CLL细胞单次静脉输注对中间或高危疾病患者的安全性。这项临床试验和初步体外研究的令人鼓舞的结果支持了以下假设：可以将与CLL相关的抗原识别为宿主T细胞，并可能由宿主CTL靶向，从而导致CLL细胞的免疫清除。为了剖析对假定CLL相关抗原的自发和诱导的细胞反应，我们具有以下特定目的。 （1）检查在CLL研究联盟（CRC）开发的疗法中，在诊断和治疗前和治疗后，患者血液T细胞的表达的T细胞受体VBETA曲目表达的T细胞受体曲目（CRC）。 （2）在类似的时间点上评估血液T细胞的前体频率，这些时间点可以响应于ADCD154-CLL，或在体外CD3/CD28绑扎后响应ADCD154-CLL或自体CLL细胞。 （3）定义了由该提案的项目1中与CLL有关的基因编码的肽，这些肽可以用作潜在的抗原。 （4）在可以识别和分离编码肿瘤相关抗原的基因的策略中使用自体CLL细胞反应的T细胞系。 （5）开发了一项II期CRC试验基因疗法，涉及自体ADCD154-CLL细胞多次输注。通过这些研究，我们确定了与CLL相关的抗原，并为该疾病开发了新型的基于免疫的疗法。