Immunotherapy for Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病的免疫治疗

基本信息

批准号：
7070074
负责人：
JANUARIO E CASTRO
金额：
$ 13.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-21 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7070074
关键词：
2&apos 3&apos dideoxynucleoside Adenoviridae B lymphocyte CD1 molecule antigen presentation chronic lymphocytic leukemia clinical research clone cells combination cancer therapy cytotoxic T lymphocyte enzyme linked immunosorbent assay flow cytometry histocompatibility antigens human tissue immunomodulators interferon gamma leukocyte activation /transformation leukocyte count neoplasm /cancer immunotherapy oligonucleotides peptide library therapy design /development western blottings

2&apos 3&apos dideoxynucleoside Adenoviridae B lymphocyte CD1 molecule antigen presentation chronic lymphocytic leukemia clinical research clone cells combination cancer therapy cytotoxic T lymphocyte enzyme linked immunosorbent assay flow cytometry histocompatibility antigens human tissue immunomodulators interferon gamma leukocyte activation /transformation leukocyte count neoplasm /cancer immunotherapy oligonucleotides peptide library therapy design /development western blottings

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项目摘要

DESCRIPTION (provided by applicant): Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults and is characterized in many cases by a progressive clinical course in which conventional treatments, such as chemotherapy, may palliate symptoms but unfortunately do not provide an established cure. Therefore, there is an urgent need for new and more effective therapeutic strategies that involve different mechanisms of action. Several features of this disease suggest that immune-based strategies may have therapeutic potential. Therefore, our group has developed strategies that enhance the ability of CLL cells to interact with T cells and promote effective anti-leukemia responses through a mechanism of Enhanced Antigen Presentation. One is the use of in vitro transduction of CLL cells using adenovirus encoding CD154 (Ad-CD154). This approach has proven to be effective in a recently completed clinical trial in which patients treated with this modality had increased T cell counts, decreased lymph node size and fewer circulating leukemia cells. A second immune-based strategy in CLL is the use of DNA oligodeoxynucleotides (ODN), which activates CLL cells, enhances their function as antigen presenting cells and most importantly improves infectibility and transgene expression of Ad-CD 154. The proposal presented here will investigate the mechanism of ODN mediated activation in CLL cells and the potential synergistic effect in combination with Ad-CD154. Also, we will use this model of Enhanced Antigen Presentation to expand and clone reactive/cytolytic anti-leukemia T cells from CLL patients. Using Positional Scanning Synthetic Combinatorial Peptide Libraries, we propose to characterize specific peptide ligands to those reactive/cytolytic T cells.

描述（由申请人提供）：慢性淋巴细胞性白血病（CLL）是成年人中最常见的白血病，在许多情况下是由渐进式临床过程所表现的，在许多情况下，传统治疗（例如化学疗法）可能会抑制症状，但不幸的是不能提供既定的治疗方法。因此，迫切需要采取新的，更有效的治疗策略，涉及不同的作用机制。该疾病的一些特征表明，基于免疫的策略可能具有治疗潜力。因此，我们的小组制定了通过增强的抗原表现的机制来增强CLL细胞与T细胞相互作用并促进有效抗白血病反应的能力的策略。一种是使用编码CD154（AD-CD154）的腺病毒在体外转导CLL细胞的使用。事实证明，这种方法在最近完成的临床试验中有效，在该试验中，使用这种方式治疗的患者T细胞计数增加，淋巴结大小降低和循环中的白血病细胞较少。 CLL中的第二种免疫策略是激活CLL细胞的DNA寡脱氧核苷酸（ODN）的使用，可以增强其作为抗原呈现细胞的功能，最重要的是改善了AD-CD 154的传染性和转基因表达。这里提出的建议将研究CLL细胞中ODN介导的激活的机理，并与AD-CD154结合使用潜在的协同作用。此外，我们将使用这种增强抗原表现的模型来扩展和克隆反应性/细胞溶质性抗白血病T细胞，来自CLL患者。使用位置扫描合成组合肽库，我们建议将特定的肽配体表征为那些反应性/溶质性T细胞。