Lymphoma Therapy with Reprogrammed Measles Viruses

描述(申请人提供)：病毒可以作为进入和复制癌细胞的目标，并武装起来放大传统化疗或放射治疗的效果。特别是，由于淋巴瘤缓解是在急性麻疹后记录的，重新编程的麻疹病毒(MV)似乎是治疗对常规治疗无效的淋巴瘤患者的理想方法。我们已经证明了疫苗系MV在淋巴瘤异种移植模型中的溶瘤效果，并表明受体靶向和前药转换酶武装提高了病毒治疗的特异性和有效性。然而，肿瘤的消退是暂时的。我们现在计划评估目标和武装的替代方式的效力。在细胞进入靶向方面，我们将比较不同受体特异性的MV在淋巴瘤患者临床材料中的感染效果，包括肿瘤组织和循环细胞。至于进入后的靶向，我们将通过其固有免疫控制蛋白的特定缺陷来产生具有优先复制潜力的MV。我们将通过表达钠碘转运体(NIS)蛋白来武装MV，允许131I的浓度。这些病毒的疗效将与表达前药物转换酶嘌呤核苷酸磷酸化酶(PNP)的病毒的疗效进行比较，PNP可激活淋巴瘤化疗药物氟达拉滨磷酸(F-araAMP)。为了保护载体免受MV中和抗体的影响，我们将用其他副粘病毒的结构相关但无交叉反应的包膜覆盖MV核糖核壳。我们将测试重组病毒感染淋巴瘤患者细胞的效果，以及减少包括套细胞淋巴瘤在内的不同类型淋巴瘤的异种移植的效果。我们将在移植了同种异体肿瘤的免疫活性小鼠身上测试连续应用不同包膜的病毒的溶瘤效果。 公共卫生相关性：这项拨款申请预见了将一种自然嗜淋巴的人类病毒重新编程为治疗淋巴瘤的药物。我们将开发补充的实验途径来重新编程麻疹病毒：增加不同层次的癌细胞特异性(靶向)，增强效力(武装)，并保护病毒成为宿主免疫系统的治疗媒介。

DESCRIPTION (provided by applicant): Viruses can be targeted for entry and replication in cancer cells and armed to amplify the effects of conventional chemo- or radiation therapy. In particular, since lymphoma remissions were documented after acute measles, reprogrammed measles viruses (MV) appear ideal to treat lymphoma patients failing to respond to conventional therapies. We have already proven the oncolytic efficacy of vaccine-lineage MV in lymphoma xenograft models, and have shown that receptor-targeting and prodrug convertase-arming enhances specificity and efficacy of virotherapy. Tumor regressions, however, were temporary. We now plan to assess the efficacy of alternative modalities of targeting and arming. As to cell-entry targeting, we will compare the infection efficacy of MV with different receptor specificity in clinical materials from lymphoma patients including tumor tissue and circulating cells. As to post-entry targeting, we will generate MV with the potential of preferential replication through specific defects in their innate immunity control proteins. We will arm MV by expression of the natrium-iodine symporter (NIS) protein, allowing concentration of 131I. The efficacy of these viruses will be compared with that of viruses expressing the prodrug convertase purine nucleotide phosphorylase (PNP), activating the lymphoma chemotherapeutic fludarabine phosphate (F-araAMP). To shield vectors from MV-neutralizing antibodies, we will cover the MV ribonucleocapsid with the structurally related but non-cross-reactive envelopes of other paramyxoviruses. We will test the efficacy of reprogrammed viruses in infecting cells of lymphoma patients, and in reducing xenografts of different lymphoma types, including mantle cell lymphoma. We will test the oncolytic efficacy of sequential application of viruses with alternative envelopes in immunocompetent mice with implanted congenic tumor allografts. PUBLIC HEALTH RELEVANCE: This grant application foresees to reprogram a human virus that is naturally lymphotropic into a lymphoma therapeutic. We will develop complementary avenues of experimentation to reprogram measles virus: adding different layers of cancer cell specificity (targeting), enhancing potency (arming), and shielding the virus turned into a therapeutic vector from the host immune system.