Mechanisms of Serotherapy of B-Cell Malignancies

使用利妥昔单抗的非霍奇金淋巴瘤（NHL）的血清疗法彻底改变了裸抗体在淋巴瘤中的使用。 癌症的治疗。然而，即使取得了这一成功，仍然有许多关于其作用机制的问题，如果更多的 已知，可以帮助改善或开发类似的相对无毒的治疗方法， 和其它B细胞恶性肿瘤。在这方面，我们假设抗肿瘤活性 靶特异性裸MAb的表达可以通过以下一种或多种手段来增强： （B）通过同时使用G-CSF或GM-CSF激活自然杀伤（NK）细胞 免疫调节药物（DvliD）;（c）PS341（bortezimib）对蛋白酶体-泛素系统的抑制;（d） 使用反义寡核苷酸（阿索）降低Bcl-2抗凋亡蛋白的表达。另外，我们假设 利妥昔单抗耐药的获得与以下因素有关：a） 不同的利妥昔单抗抗性细胞系和来自证明临床利妥昔单抗抗性的患者的原代淋巴瘤细胞; B）CD 20结构的结构变化导致CD 20抗原重新分布到脂筏中的异常， 下行信号。这些假设是本项目的基础。探讨其作用机制 利妥昔单抗将部分地通过几种利妥昔单抗抗性细胞系的开发而得到帮助。这一承诺是可能的 这主要是由于本计划项目中几位研究人员的合作和协作，包括 罗斯威尔公园癌症中心和福克斯蔡斯癌症中心。因此，该项目具有独特的定位，以评估所有 这些问题的目的是最终利用这项研究中获得的见解来开发更好的治疗策略， 这将在临床上进行测试，并可能导致未来B细胞恶性肿瘤治疗方式的重要变化。

Serotherapy of non-Hodgkin's lymphoma (NHL) using rituximab has revolutionized the use of naked antibodies in the treatment of cancer. Yet even with this success, there are still many questions about its mechanism of action that, if more were known, could aid in the improvement of or the development of similar relatively non-toxic approaches for treating this and other B-cell malignancies with rituximab or other antibodies. In this regard, we hypothesize that the anti-tumor activity of target-specific naked MAbs can be enhanced by one or more of the following means: (a) Stimulation of mononuclear cells and neutrophils using G-GSF or GM-CSF; (b) Natural killer (NK) cell activation via the concomitant use of immunomodulatory drugs (DvliDs); (c) Inhibition of the proteasome-ubiquitin system by PS341 (bortezimib); (d) Decreasing expression of Bcl-2 anti-apoptotic protein using antisense oligonucleotides (ASO). In addition, we hypothesize that the acquirement of resistant to rituximab is associated with: a) common gene expression profile changes between different rituximab-resistant cell lines and on primary lymphoma cells from patients demonstrating clinical rituximabresistance; b) structural changes in CD20 structure leads to abnormalities in CD20 antigen redistribution into lipid rafts and downstream signaling. These hypotheses serve as a basis for this project. An investigation of the mechanism of action of rituximab will be aided in part by the development of several rituximab-resistant cell lines. This undertaking is possible primarily because of the cooperation and collaboration of several investigators within this Program Project, including Roswell Park Cancer Center and at Fox Chase Cancer Center. Thus, this project is uniquely positioned to evaluate all of these issues with the intent to ultimately use the insights gained in this research to develop better treatment strategies that can be tested clinically, and which could lead to important changes in the way B-cell malignancies will be treated in the future.