Lymphoma Therapy with Reprogrammed Measles Viruses

描述（由申请人提供）：病毒可以靶向进入癌细胞并在癌细胞中复制，并增强常规化疗或放疗的效果。特别是，由于淋巴瘤缓解是在急性麻疹后记录的，重编程麻疹病毒（MV）似乎是治疗对常规治疗无效的淋巴瘤患者的理想药物。我们已经证明了疫苗谱系MV在淋巴瘤异种移植模型中的溶瘤功效，并且已经表明受体靶向和前药转化酶武装增强了病毒治疗的特异性和功效。然而，肿瘤消退是暂时的。我们现在计划评估选择目标和武装的替代方式的效力。至于细胞进入靶向，我们将比较具有不同受体特异性的MV在来自淋巴瘤患者的临床材料（包括肿瘤组织和循环细胞）中的感染功效。至于进入后靶向，我们将通过其先天免疫控制蛋白中的特定缺陷产生具有优先复制潜力的MV。我们将通过表达钠碘同向转运体（NIS）蛋白来武装MV，从而使131 I浓缩。将这些病毒的功效与表达前药转化酶嘌呤核苷酸磷酸化酶（PNP）的病毒的功效进行比较，所述前药转化酶嘌呤核苷酸磷酸化酶（PNP）激活淋巴瘤化疗药物磷酸氟达拉滨（F-araAMP）。为了屏蔽MV中和抗体的载体，我们将用其他副粘病毒的结构相关但非交叉反应性的包膜覆盖MV核糖核衣壳。我们将测试重编程病毒在感染淋巴瘤患者细胞和减少不同淋巴瘤类型（包括套细胞淋巴瘤）异种移植物中的功效。我们将在植入同种异体肿瘤移植物的免疫活性小鼠中测试顺序应用具有交替包膜的病毒的溶瘤功效。

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.