Impact of Chemo-Immunotherapy in Relapsed/Refactory B-CLL

化疗免疫疗法对复发/难治性 B-CLL 的影响

• 批准号: 7094628
• 负责人: Neil E Kay
• 金额: $ 39.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094628
• 关键词: clinical research; genes; immunotherapy; microRNAs; model; monoclonal antibody

DESCRIPTION (provided by applicant): There is a significant need for advances in the understanding of the biology of the leukemic CLL B cell clones in this currently incurable disease. To address this, we have designed a combination chemotherapy trial utilizing two monoclonal antibodies known to have important tissue site specific impact. Rituximab and Campath, appear to synergize with chemotherapy, recognize different surface molecules on CLL B cells, and effect removal of the CLL leukemic burden from separate organ compartments. We expect this chemoimmunotherapy (CIT) approach to generate complete (CR) nodular PR or partial responses (PR) in a significant percentage, albeit not all, of relapsed patients. In this proposal, we wish to perform correlative laboratory studies on the CLL patients entering this trial. We will generate valuable, relevant information about the leukemic B cell clones in B-CLL with a variety of laboratory approaches. Our approach will allow us to a) monitor the minimal residual level of leukemic CLL B cell burden for clinical responders and their T cell repertoire status and b) study the association of biologic features, which permit elaboration of risk stratification parameters and begin to develop a prognostic model that predict response. Thus for patients who experience a CR, we will monitor for minimal residual disease (MRD) detection using detection methods that include both flow cytometry and a quantitative polymerase chain reaction assay. This will be done to ascertain if a clinical CR with or without MRD detection confers clinical advantage to the CLL patients. Because the CIT approach is likely to confer immune deficiency to these already compromised patients, we intend to monitor the extent of this by assessing blood T cell status using both flow and CDR3 spectratype analysis. The correlative laboratory tests we will determine for novel risk stratification parameters include; FISH detectable defects, immunoglobulin variable heavy region mutational status, ZAP-70 and VEGF-based autocrine pathways related to apoptosis resistance of CLL B cells and the angiogenesis status of marrow tissue in these patients. With this information we will also develop a prognostic model that can be used for more accurate counsel and stratification. Finally we intend to study microRNA expression on the CLL B cell clones. This newly defined set of genes promises to uncover genes that relate to both disease progression and use in definition of more high risk disease. This gene set will be explored for use in the developed prognostic model for CLL patients. We hypothesize that this trial will generate significant responses in more aggressive CLL, that we will be able to extend the utility of selected risk stratification parameters for CLL patients and generate further insight into the biology of CLL B cells.

描述（由申请人提供）：对于这种目前无法治愈的疾病中白血病 CLL B 细胞克隆的生物学的理解，迫切需要取得进展。为了解决这个问题，我们设计了一项联合化疗试验，利用两种已知具有重要组织部位特异性影响的单克隆抗体。 Rituximab 和 Campath 似乎与化疗具有协同作用，识别 CLL B 细胞上的不同表面分子，并有效消除不同器官区室中的 CLL 白血病负担。我们预计这种化学免疫疗法 (CIT) 方法能够在相当比例（尽管不是全部）的复发患者中产生完全 (CR) 结节性 PR 或部分缓解 (PR)。在本提案中，我们希望对进入本试验的 CLL 患者进行相关的实验室研究。我们将通过各种实验室方法生成有关 B-CLL 中白血病 B 细胞克隆的有价值的相关信息。我们的方法将使我们能够 a) 监测临床反应者白血病 CLL B 细胞负荷的最低残留水平及其 T 细胞库状态，b) 研究生物学特征的关联，这允许详细说明风险分层参数并开始开发预测反应的预后模型。因此，对于经历 CR 的患者，我们将使用包括流式细胞术和定量聚合酶链反应测定在内的检测方法来监测微小残留病 (MRD) 检测。这样做是为了确定有或没有 MRD 检测的临床 CR 是否能为 CLL 患者带来临床优势。由于 CIT 方法可能会给这些已经受损的患者带来免疫缺陷，因此我们打算通过使用流式和 CDR3 谱分析评估血液 T 细胞状态来监测其程度。我们将为新的风险分层参数确定的相关实验室测试包括： FISH 可检测缺陷、免疫球蛋白重链可变区突变状态、与 CLL B 细胞凋亡抵抗相关的基于 ZAP-70 和 VEGF 的自分泌途径以及这些患者骨髓组织的血管生成状态。有了这些信息，我们还将开发一个预后模型，可用于更准确的建议和分层。最后，我们打算研究 CLL B 细胞克隆上的 microRNA 表达。这组新定义的基因有望揭示与疾病进展相关的基因并用于定义更高风险的疾病。该基因集将被探索用于开发的 CLL 患者预后模型。我们假设这项试验将在更具侵袭性的 CLL 中产生显着的反应，我们将能够扩展 CLL 患者选定的风险分层参数的效用，并进一步深入了解 CLL B 细胞的生物学。