Treatment of multiple myeloma using oncolytic myxoma virus

 描述（由申请人提供）：溶瘤病毒，例如兔特异性粘液瘤病毒（MYXV），代表了治疗癌症患者的有前途的新方法。虽然溶瘤药物领域传统上专注于实体瘤，但我们最近的数据表明，MYXV 还可以有效治疗造血系统恶性肿瘤多发性骨髓瘤。具体来说，MYXV 根据差异结合区分骨髓瘤细胞和正常细胞，并随后通过诱导快速凋亡反应来消除这些细胞。这导致 MYXV 疗法完全预防与自体移植样本污染相关的骨髓瘤复发，并通过明显的免疫学机制根除体内残留的骨髓瘤。 不幸的是，由于缺乏对治疗机制的了解，目前这种有希望的疗法的转化受到阻碍。这种缺乏了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，我们提出了当前的提案，旨在通过确定介导的分子机制来推进 MYXV 在临床环境中的使用：1）通过全身性 MYXV 治疗诱导抗骨髓瘤免疫反应，2）介导骨髓瘤细胞对 MYXV 治疗耐药的机制，以及 3）病毒结合在将 MYXV 递送至残留疾病部位中所起的作用。 该项目的成功完成可能会以多种方式对公众健康产生重大影响。首先，它将促进 MYXV 作为治疗骨髓瘤患者的有前途的疗法的使用。此外，该提案中产生的信息可通过揭示介导成功体内治疗的机制来改善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.