Radiovirotherapy for Multiple Myeloma

描述（由申请人提供）：多发性骨髓瘤是一种播散性浆细胞恶性肿瘤，目前的治疗方法无法治愈，每年导致10,000美国人死亡。我们最近发现，减毒麻疹病毒对SCID小鼠生长的人类骨髓瘤细胞和骨髓瘤异种移植物都有选择性溶瘤作用。此外，在复发性多发性骨髓瘤患者中，全身麻疹病毒递送是高度可行的，因为他们的体液免疫受到严重抑制，抗麻疹病毒抗体滴度低，无保护性。因此，麻疹减毒病毒是治疗复发性骨髓瘤的一种很有前途的实验药物。

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.