Antibody Neutralization of Therapeutic Viruses

多发性骨髓瘤是一种无法治愈的、播散性的终末分化浆细胞恶性肿瘤，它将是 对2006年11,000多名美国人的死亡负有责任。减毒麻疹病毒是有选择性的 对大量表达CD46(病毒受体)的人骨髓瘤浆细胞具有破坏性 在小鼠骨髓瘤异种移植模型中的治疗作用。因此，我们正在测试一种重组麻疹 晚期难治性多发性骨髓瘤患者静脉注射病毒。 中和抗麻疹抗体预计会限制系统性治疗麻疹的疗效 接种麻疹病毒，特别是在抗体效价较高的70%的骨髓瘤患者中。这个 这项建议的目标是制定最佳策略，以对抗血液中和麻疹病毒。 通过抑制抗麻疹抗体的产生，或通过将病毒传递到自体体内 单核细胞或树突状细胞，在体外感染。这些研究的结果将被用于指导 骨髓瘤患者麻疹病毒治疗的未来临床试验设计。具体目标如下： 目的1.开发一种临床可行的策略，将环磷酰胺与麻疹增强剂联合使用 接种疫苗可降低血浆中和抗麻疹抗体浓度。 目的2.评估麻疹感染的单核细胞或单核细胞来源的树突状细胞的性能 (未成熟或成熟)作为抗抗体病毒的传递载体。 目的3.确定抑制CCR7趋化因子受体的表达是否有利地影响 麻疹感染树突状细胞在CD46转基因SCID小鼠体内的生物分布抗体是病毒作为抗癌剂成功部署的最重要障碍。这 格兰特试图为这个问题开发临床上可行的解决方案。

Multiple myeloma is an incurable, disseminated malignancy of terminally differentiated plasma cells that will be responsible for the deaths of more than 11,000 Americans in 2006. Attenuated measles viruses are selectively destructive to human myeloma plasma cells which express abundant CD46 (the viral receptor) and are therapeutically potent in murine myeloma xenograft models. We are therefore testing a recombinant measles virus by intravenous administration in patients with advanced, treatment-refractory multiple myeloma. Neutralizing antimeasles antibodies are expected to limit the therapeutic efficacy of the systemically administered measles viruses, particularly in those 70% of myeloma patients with higher antibody titers. The goal of this proposal is to develop optimal strategies to combat measles virus neutralization in the bloodstream by suppressing the production of antimeasles antibodies, or by delivering the virus inside autologous monocytes or dendritic cells, infected outside the body. The findings of these studies will be used to guide the design of future clinical trials of measles virotherapy in myeloma patients. Specific aims are as follows: Aim 1. Develop a clinically viable strategy using cyclophosphamide in combination with measles booster vaccination to reduce the plasma concentration of neutralizing anti-measles antibodies. Aim 2. Evaluate the performance of measles-infected monocytes, or monocyte-derived dendritic cells (immature or mature) as antibody-resistant virus delivery vehicles. Aim 3. Determine whether suppression of CCR7 chemokine receptor expression can favorably impact the biodistribution of measles-infected dendritic cells in CD46 transgenic SCID mice. Antibodies are the most important barrier to the successful deployment of viruses as anticancer agents. This grant seeks to develop clinical viable solutions to this problem.