Immunotherapy for Chronic Lymphocytic Leukemia

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是成人中最常见的白血病，在许多情况下，其特征在于进行性临床病程，其中常规治疗（如化疗）可缓解症状，但不幸的是不能提供确定的治愈方法。因此，迫切需要涉及不同作用机制的新的和更有效的治疗策略。 这种疾病的几个特征表明，基于免疫的策略可能具有治疗潜力。因此，我们的小组已经开发出增强CLL细胞与T细胞相互作用的能力并通过增强的抗原呈递机制促进有效的抗白血病应答的策略。一种是使用编码CD 154的腺病毒（Ad-CD 154）体外转导CLL细胞。在最近完成的一项临床试验中，这种方法被证明是有效的，在该试验中，用这种方法治疗的患者T细胞计数增加，淋巴结大小减少，循环白血病细胞减少。CLL中的第二种基于免疫的策略是使用DNA寡脱氧核苷酸（ODN），其激活CLL细胞，增强其作为抗原呈递细胞的功能，并且最重要的是改善Ad-CD 154的感染性和转基因表达。 本研究旨在探讨ODN介导的CLL细胞活化机制及其与Ad-CD 154联合应用的潜在协同效应。此外，我们将使用这种增强的抗原呈递模型来扩增和克隆来自CLL患者的反应性/细胞溶解性抗白血病T细胞。使用位置扫描合成组合肽库，我们建议表征那些反应性/细胞溶解性T细胞的特异性肽配体。

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.