Radiovirotherapy for Multiple Myeloma

描述(申请人提供)：多发性骨髓瘤，每年导致10,000名美国人死亡，是一种播散性浆细胞恶性肿瘤，目前的治疗方法无法治愈。我们最近发现，减毒麻疹病毒对人骨髓瘤细胞和在SCID小鼠中生长的骨髓瘤异种移植瘤都具有选择性的溶瘤作用。此外，系统性麻疹病毒对复发性多发性骨髓瘤患者是非常可行的，因为它们对体液免疫有很大的抑制作用，而且抗麻疹病毒抗体效价低，没有保护性。因此，减毒麻疹病毒是治疗复发性骨髓瘤的一种有前途的实验药物。 这项提案涉及的关键问题是免疫抑制的骨髓瘤患者存在溶瘤麻疹病毒过度传播的风险，瘤内病毒传播可能不足以成功治疗的相反可能性，以及需要一种非侵入性策略来监测病毒在接受治疗的患者中的传播。由于多发性骨髓瘤是已知的最高放射敏感性的恶性肿瘤之一，我们已经产生了表达甲状腺钠碘转运体(NIS)的重组麻疹病毒，NIS是一种将放射性碘输送到哺乳动物细胞的膜离子通道。这种新型的溶瘤工程麻疹病毒被命名为MV-NIS。将在拟议的研究中测试的MV-NIS病毒的假设如下： 1.受MV-NIS感染的骨髓瘤细胞对放射性碘的摄取将增强，从而可以无创地进行活体伽马相机成像，以估计感染病毒的细胞的数量和分布。 2.MV-NIS感染细胞摄取~(125)I，释放低能俄歇电子，可介导对病毒感染的骨髓瘤细胞的快速杀伤，无旁观者杀伤，从而终止病毒传播。 3.MV-NIS感染细胞摄取~(131)I，对感染的骨髓瘤细胞和未感染的邻近细胞均造成损害，从而以剂量依赖的方式改变病毒扩散的动力学。 4.在正确掌握131I给药剂量和时机的前提下，MV-NIS放射病毒治疗的疗效将大于单纯MV-EDM病毒治疗的疗效。

DESCRIPTION (provided by applicant): Multiple myeloma, which is responsible for the deaths of 10,000 Americans annually, is a disseminated plasma cell malignancy, not curable with current therapy. We recently discovered that attenuated measles viruses are selectively oncolytic for both human myeloma cells and myeloma xenografts grown in SCID mice. Moreover, systemic measles virus delivery is highly feasible in patients with relapsed multiple myeloma because they have profound suppression of humoral immunity and low, nonprotective titers of antimeasles virus antibody. Attenuated measles virus is therefore a promising experimental agent for treatment of relapsed myeloma. Key issues addressed in this proposal are the risk of excessive spread of oncolytic measles virus in the immunosuppressed myeloma patient, the contrary possibility that intratumoral virus spread may be inadequate for successful therapy, and the need for a noninvasive strategy to monitor virus spread in the treated patient. Since multiple myeloma is one of the most highly radiosensitive malignancies known, we have generated recombinant measles viruses expressing the thyroidal sodium iodide symporter (NIS), a membrane ion channel that transports radioactive iodine into mammalian cells. This novel oncolytic engineered measles virus has been named MV-NIS. Hypotheses regarding the MV-NIS virus that will be tested in the proposed studies are as follows: 1. Radioiodine uptake will be enhanced in myeloma cells infected by MV-NIS, allowing noninvasive in vivo gamma camera imaging to estimate the number and distribution of virus-infected cells. 2. Uptake by MV-NIS infected cells of 125I, which emits low energy Auger electrons, will mediate rapid killing of virus infected myeloma cells, with no bystander killing and will thereby terminate virus spread. 3. Uptake by MV-NIS infected cells of 131I, a beta-emitting isotope, will modify the kinetics of virus spread in a dose-dependent manner by damaging both infected myeloma cells and uninfected neighboring cells. 4. With correct tailoring of the dose and timing of 131I administration the therapeutic benefit of MV-NIS radiovirotherapy will be greater than the benefit of MV-Edm virotherapy alone.