Reolysin-based combination therapy in relapsed multiple myeloma

项目摘要 多发性骨髓瘤（MM）是一种无法治愈的血液癌症，是第二常见的血液癌症。 大多数患者在诊断后5年内死亡，因此迫切需要开发药物， 新的行动机制。使用Reolysin（人呼肠孤病毒（RV）的可输注形式）的病毒溶瘤疗法， 由骨髓瘤的广泛临床前数据支持，其抗肿瘤活性由直接 细胞溶解和针对感染的MM细胞的免疫应答。我们的I期单药治疗中的复发MM患者 RV试验耐受性良好，RV选择性进入MM癌细胞。无论病毒的生产力如何 未观察到与肿瘤细胞死亡相关的感染。我们随后的1b期RV试验加上 蛋白酶体抑制剂（PI）卡非佐米（CFZ）在12例可评价患者中的11例中显示出客观反应， 这是单靠CFZ无法达到的效果。重要的是，入组1b期研究的MM患者 也对PI硼替佐米（BTZ）耐药，因此他们对RV+CFZ的客观反应是非常 取得了令人鼓舞目前尚不清楚与化疗药物联合使用时增强的RV活性是否 由于增加的生产性感染、增强的免疫应答或两者。的长期目标 本项目旨在优化RV在MM患者中的抗癌活性。我们的总体目标是 实现我们目标的一步是通过增强MM细胞的容许性来增加RV对MM细胞的杀伤 到RV。我们的中心假设是，RV临床疗效将通过添加CFZ和/或 HDACi由于它们能够增加RV可及性和癌细胞的感染效率。我们将测试我们的 中心假设，并通过以下目的实现我们的目标：（1）测试的安全性和有效性 在复发性MM患者中进行的1b期试验中，Reolysin与蛋白酶体抑制剂卡非佐米联合使用;（2）评估 蛋白酶体抑制在调节先天免疫应答和增加RV感染MM的杀伤中的作用 （3）在体外和NOD-SCID小鼠中测量肿瘤对向RV±PI添加HDACi的敏感性。我们 将证实基于Reolysin的方案不仅将增强MM细胞中的生产性病毒感染， 瞬时抑制浸润性细胞毒性T淋巴细胞并抑制先天性抗病毒IFN应答。与 完成这项工作后，我们将推出一种全新的，高效的治疗方法，并提供 机械数据，以建立在其成功的组合。

PROJECT SUMMARY Multiple myeloma (MM) is an incurable blood cancer and is the second most common hematologic cancer. The majority of patients die within 5 years of diagnosis, hence there is an urgent need to develop drugs with new mechanisms of action. Viral oncolytic therapy with Reolysin, the infusible form of human reovirus (RV), is supported by extensive preclinical data in myeloma with its antitumor activity driven by a combination of direct cytolysis and immune responses against infected MM cells. Relapsed MM patients in our phase 1 single agent RV trial tolerated the treatment well and the RV selectively entered MM cancer cells. However productive viral infection associated with tumor cell death was not seen. Our subsequent phase 1b trial of RV plus the proteasome inhibitor (PI) Carfilzomib (CFZ) demonstrated objective responses in 11 of 12 evaluable patients, an effect that could not be achieved by CFZ alone. Importantly, MM patients enrolled in our phase 1b were also resistant to the PI bortezomib (BTZ) and hence their objective response to RV+CFZ is a very encouraging. It's not known whether the enhanced RV activity in combination with chemotherapeutic agents is due to increased productive infection, augmentation of the immune response, or both. The long-term goal of this project is to optimize the anti-cancer activity of RV in MM patients. Our overall objective, which is the next step toward attainment of our goal, is to increase RV killing of MM cells by enhancing MM cell permissiveness to RV. Our central hypothesis is that RV clinical efficacy will be potentiated by the addition of CFZ and/or HDACi due to their ability to increase RV accessibility and infection efficiency of cancer cells. We will test our central hypothesis and achieve our goals through the following aims: (1) Test the safety and efficacy of Reolysin with the proteasome inhibitor Carfilzomib in a phase 1b trial in relapsed MM patients; (2) Assess the role of proteasome inhibition in modulating the innate immune response and increase killing of RV infected MM cells; and (3) Measure tumor sensitivity to the addition of HDACi to RV±PI in vitro and in NOD-SCID mice. We will confirm that Reolysin-based regimens will enhance not only productive viral infection in MM cells, but transiently suppress infiltrating cytotoxic T-lymphocytes and suppress the innate antiviral IFN response. With completion of this work, we will have introduced an entirely novel, highly effective treatment and provided mechanistic data to build upon its success in combination.