ANTICD20 MEDIATED SIGNALING AND ANTITUMOR RESPONSE

描述：基于单克隆抗体的治疗的最新试验 在患者中表现出明确的抗肿瘤活性和最小的毒性 低级别和滤泡性B细胞恶性肿瘤 在最近完成的 试验中，大约50%的患者患有难治性疾病或 标准治疗后复发，对治疗有反应 未标记的嵌合抗CD20抗体。 尽管假设大多数 这种抗肿瘤活性与抗体依赖性细胞 细胞毒性，这种机制的直接证据很少。 越来越 大量数据表明，通过CD20的跨膜信号传导在 在控制B细胞增殖和分化中的作用。 的 申请人假设通过CD20的跨膜信号传导可能是 在抗CD20单克隆抗体治疗的临床应答中很重要。 本研究旨在评估抗CD20是否介导 从患者获得的恶性淋巴细胞中的跨膜信号传导 计划接受抗CD20抗体治疗，并确定是否 信号传导与临床反应相关。 恶性淋巴细胞会 从参加抗CD20单克隆抗体临床试验的患者中收集 在mAb给药前进行治疗。 收获的淋巴细胞将 在体外用抗-CD20或同种型匹配的对照抗体处理。 沿着信令的不同点处的各种参数的变化 将评估级联以确定跨膜信号传导是否具有 是否会导致下游的变化。 的参数 测量包括酪氨酸磷酸化，细胞内钙流， Bcl-2、Bax和Bcl-XL的信息和蛋白表达，细胞周期分析， 增殖、凋亡和免疫表型。 任何观察到的变化都将是 与抗体治疗的临床反应相关。 的检测 抗体诱导的信号传导和临床应答之间的相关性将 提供了强有力的证据表明跨膜信号传导在临床上是重要的， 并将影响下一代治疗方案的设计， 使用这种新的治疗方法。

DESCRIPTION: Recent trials of monoclonal antibody-based therapy have demonstrated clear anti-tumor activity with minimal toxicity in patients with low grade and follicular B-cell malignancies. In a recently completed trial, approximately 50 percent of patients that had refractory disease or relapsed following standard modalities of treatment responded to therapy with unlabeled chimeric anti-CD20. Although the assumption is that most of this anti-tumor activity is related to antibody dependent cellular cytotoxicity, there is little direct evidence for this mechanism. A growing body of data indicates that transmembrane signaling via CD20 plays a key role in the control of B-cell proliferation and differentiation. The applicants hypothesize that transmembrane signaling via CD20 may be important in the clinical response to anti-CD20 monoclonal antibody therapy. The current study is designed to assess whether anti-CD20 mediates transmembrane signaling in malignant lymphocytes obtained from patients scheduled to undergo anti-CD20 antibody therapy, and to determine whether signaling correlates with clinical response. Malignant lymphocytes will be harvested from patients enrolled in a clinical trial of anti-CD20 moAb therapy prior to the administration of mAb. Harvested lymphocytes will be treated in vitro with anti-CD20 or isotype-matched control antibody. Changes in a variety of parameters at different points along the signaling cascade will be assessed to determine whether transmembrane signaling has taken place, and whether it results in downstream changes. Parameters to be measured include tyrosine phosphorylation, intracellular calcium flux, Bcl-2, Bax and Bcl-XL message and protein expression, cell cycle analysis, proliferation, apoptosis and immunophenotype. Any observed changes will be correlated with clinical response to antibody therapy. The detection of a correlation between antibody-induced signaling and clinical response would supply strong evidence that transmembrane signaling is important clinically, and would impact on the design of the next generation of regimens that utilize this new therapeutic approach.