Radiovirotherapy for Multiple Myeloma

描述(申请人提供)：多发性骨髓瘤是2006年超过12,000名美国人死亡的罪魁祸首，目前的治疗方法仍然无法治愈。MV-NIS是一种针对骨髓瘤浆细胞的重组麻疹病毒，编码人甲状腺钠碘转运体NIS。感染MV-NIS的细胞在其表面膜上表达NIS蛋白，从而浓缩放射性碘。在这项资助的前五年，我们使用非侵入性成像技术研究MV-NIS在骨髓瘤异种移植模型中的传播，并使用I-131实现协同肿瘤细胞杀伤(放射病毒治疗)。我们还将NIS基因导入溶瘤性水泡性口炎病毒(VSV)平台，并将VSV-NIS用于原位同基因5TGM1骨髓瘤模型的放射病毒治疗。MV-NIS目前正在多发性骨髓瘤患者的I期临床试验中进行测试，我们计划(在未来5年的某个时候)继续进行后续临床试验，在MV-NIS之后将给予治疗剂量的I-131。在这笔赠款的下一个五年中，我们的目标是开发临床上可行的方法，以提高放射病毒治疗的治疗指数。考虑到这一目标，我们有以下具体的目标：目的1.确定由编码NIS的病毒感染的骨髓瘤沉积物中放射性碘外流的速率，以及或不加上抑制ClC(N)2氯离子通道表达的shRNA。假设放射性碘通过氯通道ClC(N)2从大多数哺乳动物细胞中逃逸，并通过限制该通道的表达而更有效地保留在骨髓瘤细胞中。目的2.确定地塞米松能否减轻I-131的骨髓毒性。假设地塞米松联合放射病毒治疗将显著降低治疗的骨髓毒性，而不会抑制病毒的传播或NIS在骨髓瘤细胞中的表达，从而改善治疗结果。目的3.确定蛋白酶体抑制剂Bortezomib是否能增强MV-NIS或VSV-NIS放射病毒治疗的溶瘤效果。假说是，在放射病毒治疗的同时，给予Bortezomib将显著增强肿瘤的放射敏感性，而不会阻碍病毒的传播或NIS在骨髓瘤细胞中的表达，从而改善治疗结果。尽管引入了新的治疗方法，多发性骨髓瘤仍然无法治愈。这笔赠款将进行的研究结合了有希望的溶瘤病毒疗法和使用放射性碘治疗这种疾病的新方法。

DESCRIPTION (provided by applicant): Multiple myeloma was responsible for the deaths of more than 12,000 Americans in 2006 and remains incurable with current therapy. MV-NIS is a recombinant measles virus that targets myeloma plasma cells and codes for the human thyroidal sodium iodide symporter, NIS. MV-NIS infected cells express the NIS protein on their surface membrane and therefore concentrate radioiodine. During the first five years of this grant we used noninvasive imaging techniques to study the spread of MV-NIS in myeloma xenograft models, and used I-131 to achieve synergistic tumor cell killing (radiovirotherapy). We also introduced the NIS gene into an oncolytic vesicular stomatitis virus (VSV) platform and used VSV-NIS for radiovirotherapy in the orthotopic syngeneic 5TGM1 myeloma model. MV-NIS is now being tested in a phase I clinical trial in patients with multiple myeloma and we plan to proceed (sometime in the next five years) to a follow-on clinical trial in which a therapeutic dose of I-131 will be administered after MV-NIS. Our goal during the next five years of this grant is to develop clinically viable approaches that will enhance the therapeutic index of radiovirotherapy. With this goal in mind, we have the following specific aims: Aim 1. To determine the rates of radioiodine efflux from myeloma deposits infected with viruses that code for NIS, plus or minus a shRNA that suppresses CLC(N)2 chloride channel expression. The hypothesis is that radioiodine escapes from most mammalian cells via the chloride channel, CLC(N)2 and can be retained more efficiently in myeloma cells by constraining the expression of this channel. Aim 2. To determine whether dexamethasone can ameliorate the bone marrow toxicity of I-131. The hypothesis is that dexamethasone, administered with radiovirotherapy will significantly decrease the bone marrow toxicity of the treatment without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Aim 3. To determine whether the proteasome inhibitor bortezomib, an approved antimyeloma drug that sensitizes myeloma cells to the lethal effects of ionizing radiation, can enhance the oncolytic potency of radiovirotherapy using MV-NIS or VSV-NIS. The hypothesis is that bortezomib, administered with radiovirotherapy will significantly enhance the radiosensitivity of the tumor without retarding the propagation of the virus or the expression of NIS in myeloma cells, and will thereby lead to improved treatment outcome. Despite the introduction of new treatments, multiple myeloma remains incurable. The studies to be pursued in this grant combine the promising novel approach of oncolytic virotherapy with the use of radioactive iodine for the treatment of this disease.