Treatment of multiple myeloma using oncolytic myxoma virus

 描述(申请人提供)：溶瘤病毒，如兔特异性粘液瘤病毒(MYXV)，代表着治疗被诊断为癌症的患者的有前途的新方法。虽然肿瘤学领域传统上主要集中在实体瘤上，但我们最近的数据表明，MYXV也可以有效地治疗恶性血液病多发性骨髓瘤。具体地说，MYXV根据不同的结合将骨髓瘤细胞与正常细胞区分开来，然后通过诱导快速的凋亡反应来消除这些细胞。这使得MYXV疗法完全防止了与自体移植样本污染相关的骨髓瘤复发，并通过一种明显的免疫学机制在体内根除了残留的骨髓瘤。不幸的是，由于缺乏对治疗机制的了解，这一有希望的疗法的翻译目前受到阻碍。这种缺乏理解引起了人们对患者反应的准确预测以及治疗产生不良事件的可能性的担忧。因此，我们提出了当前的建议，旨在通过确定以下分子机制来促进MYXV在临床上的使用：1)全身MYXV治疗诱导抗骨髓瘤免疫反应，2)介导骨髓瘤细胞对MYXV治疗的耐药性的机制，以及3)病毒结合在将MYXV运送到残留疾病部位中所起的作用。该项目的成功完成可能会以各种方式对公共卫生产生重大影响。首先，它将推动MYXV作为治疗骨髓瘤患者的一种有前景的治疗方法的使用。此外，通过阐明体内治疗成功的机制，这项建议中产生的信息可能被用于改进其他溶瘤病毒的治疗。

 DESCRIPTION (provided by applicant): Oncolytic viruses, such as the rabbit-specific myxoma virus (MYXV), represent promising, novel methods to treat patients diagnosed with cancer. While the field of oncolytics has traditionally focused on solid tumors, our recent data demonstrates that the MYXV can also effectively treat the hematopoietic malignancy multiple myeloma. Specifically, MYXV discriminates myeloma cells from normal cells based on differential binding and subsequently eliminates these cells by inducing a rapid apoptotic response. This results in MYXV therapy completely preventing myeloma relapse associated with contamination of autologous transplant samples as well as eradicating residual myeloma in vivo through an apparent immunological mechanism. Unfortunately, the translation of this promising therapy is currently prevented by a lack of understanding concerning the mechanisms involved in treatment. This lack of understanding raises concerns about the accurate prediction of patient responses as well as the potential for treatment to generate adverse events. We therefore put forth the current proposal designed to advance the use of MYXV in a clinical setting by identifying the molecular mechanisms mediating: 1) the induction of an anti-myeloma immune response by systemic MYXV treatment, 2) the mechanisms mediating resistance of myeloma cells to MYXV therapy, and 3) the role that viral binding plays in delivery of MYXV to sites of residual disease. The successful completion of this project could have a significant impact on public health in a variety of ways. First it would advance the use of MYXV as a promising therapeutic for the treatment of patients with myeloma. Additionally, information generated in this proposal might be used to improve treatments with other oncolytic viruses by shedding light on the mechanisms mediating successful in vivo therapy.