ANTICD20 MEDIATED SIGNALING AND ANTITUMOR RESPONSE

描述：最近以单抗为基础的治疗试验 在患者身上表现出明显的抗肿瘤活性，毒性最小 伴有低度恶性和滤泡性B细胞恶性肿瘤。在最近完成的一个 试验中，大约50%的患有难治性疾病或 根据标准治疗方式复发，对治疗有反应 用未标记的嵌合抗CD20。尽管假设大多数人 这种抗肿瘤活性与抗体依赖的细胞有关。 细胞毒性，但几乎没有直接证据表明这一机制。一个不断增长的 大量数据表明，通过CD20传递的跨膜信号起着关键作用 在控制B细胞增殖和分化中的作用。这个 申请者假设通过CD20的跨膜信号可能是 在抗CD20单抗治疗的临床反应中具有重要意义。 目前的研究旨在评估抗CD20抗体是否在 患者外周血中恶性淋巴细胞的跨膜信号 计划接受抗CD20抗体治疗，并确定是否 信号转导与临床反应相关。恶性淋巴细胞将会 取自参加抗CD20单抗临床试验的患者 在注射单抗之前进行治疗。收获的淋巴细胞将被 体外用抗CD20抗体或同型相合对照抗体处理。 信令沿线不同点处各种参数的变化 将评估级联以确定跨膜信号是否具有 以及它是否会导致下游的变化。参数应为 测量的指标包括酪氨酸磷酸化，细胞内钙离子流量， BCL-2、Bax、BclxL信使和蛋白表达，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。检测到一个 抗体诱导的信号转导与临床反应的相关性 提供了强有力的证据表明跨膜信号在临床上很重要， 并将对下一代方案的设计产生影响 利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.