Lymphoma Therapy with Reprogrammed Measles Viruses

描述（由申请人提供）：病毒可以靶向进入和复制癌细胞，并增强常规化疗或放疗的效果。特别是，由于急性麻疹后有淋巴瘤缓解的记录，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选择。我们已经在淋巴瘤异种移植模型中证明了疫苗系MV的溶瘤效果，并表明受体靶向和药物前转化酶解除增强了病毒治疗的特异性和有效性。然而，肿瘤消退是暂时的。我们现在计划评估其他瞄准和武装方式的效果。在细胞进入靶向方面，我们将比较不同受体特异性的MV在淋巴瘤患者肿瘤组织和循环细胞等临床材料中的感染效果。至于进入后靶向，我们将通过其先天免疫控制蛋白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调体（NIS）蛋白来武装MV，使其浓度达到131I。这些病毒的疗效将与表达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）的病毒进行比较。为了保护载体免受MV中和抗体的侵害，我们将用其他副粘病毒的结构相关但不交叉反应的包膜覆盖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中的功效，以及减少不同淋巴瘤类型（包括套细胞淋巴瘤）的异种移植物的功效。我们将在植入同种异体同源肿瘤移植物的免疫功能小鼠中，测试不同包膜序列应用病毒的溶瘤效果。

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.