Radiovirotherapy for Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤是一种弥漫性浆细胞恶性肿瘤，每年导致10，000名美国人死亡，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生长在SCID小鼠中的骨髓瘤异种移植物都具有选择性溶瘤作用。 此外，全身性麻疹病毒输送在复发性多发性骨髓瘤患者中是高度可行的，因为他们具有严重的体液免疫抑制和抗麻疹病毒抗体的低、非保护性滴度。 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。 本提案中涉及的关键问题是溶瘤麻疹病毒在免疫抑制的骨髓瘤患者中过度传播的风险，相反的可能性，即瘤内病毒传播可能不足以成功治疗，以及需要一种非侵入性策略来监测治疗患者中的病毒传播。 由于多发性骨髓瘤是已知的最高度放射敏感的恶性肿瘤之一，我们已经产生了表达甲状腺钠碘同向转运体（NIS）的重组麻疹病毒，这是一种将放射性碘转运到哺乳动物细胞的膜离子通道。 这种新的溶瘤工程麻疹病毒已被命名为MV-NIS。 关于将在拟定研究中检测的MV-NIS病毒的假设如下： 1. MV-NIS感染的骨髓瘤细胞的放射性碘摄取将增强，允许非侵入性体内伽马照相机成像来估计病毒感染细胞的数量和分布。 2. MV-NIS感染的细胞对125 I（其发射低能俄歇电子）的摄取将介导病毒感染的骨髓瘤细胞的快速杀伤，而没有旁观者杀伤，从而将终止病毒传播。 3. MV-NIS感染的细胞对131 I（一种β发射同位素）的摄取将通过损伤感染的骨髓瘤细胞和未感染的邻近细胞以剂量依赖性方式改变病毒传播的动力学。 4.通过正确调整131 I给药的剂量和时间，MV-NIS放射病毒疗法的治疗益处将大于单独MV-Edm病毒疗法的益处。

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.