A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma.
A phase I trial of single-agent reolysin in patients with relapsed multiple myeloma.
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DOI：
10.1158/1078-0432.ccr-14-1404
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发表时间：
2014-12-01
期刊：
影响因子：
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通讯作者：
Hofmeister CC
中科院分区：
文献类型：
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作者：
Sborov DW;Nuovo GJ;Stiff A;Mace T;Lesinski GB;Benson DM Jr;Efebera YA;Rosko AE;Pichiorri F;Grever MR;Hofmeister CC
Reolysin®，一种呼肠孤病毒3型Dearing的专有分离物，进入并优先诱导恶性细胞的凋亡。RAS途径激活与更有效的呼肠孤病毒感染性和增强的溶瘤作用相关。呼肠孤病毒目前处于晚期实体瘤1 - 2期试验中;尚未在血液恶性肿瘤患者中进行临床试验。一项1期试验以两种剂量水平治疗了12例复发性骨髓瘤患者。Reolysin每天输注，每28天输注5天。在筛选和第1周期第8天，通过原位杂交（ISH）检查骨髓标本中的CD 138、p38、半胱天冬酶-3、呼肠孤病毒RNA和衣壳蛋白。在患者样本和MM细胞系中评价了连接粘附分子1（JAM-1）和癌症上调基因2（CUG 2）。在周期1期间每周进行中和抗呼肠孤病毒抗体（奈良）测定。无剂量限制性毒性（DLT），患者在第1-5天剂量水平达到每日3 x 1010 TCID 50，3级实验室毒性包括中性粒细胞减少症、血小板减少症和低磷血症。原位杂交证明呼肠孤病毒基因组局限于MM细胞中。呼肠孤病毒衣壳蛋白和caspase-3很少在呼肠孤病毒RNA阳性细胞中鉴定。病情稳定的最长持续时间为4、5和8个月。用单药Reolysin治疗耐受性良好，并且与嗜酸性呼肠孤病毒RNA骨髓瘤细胞进入相关，但在MM细胞内仅产生最小的细胞内呼肠孤病毒蛋白。我们的数据支持在MM细胞中，Reolysin诱导的溶瘤作用需要联合治疗，与其他癌症相似。
Reolysin®, a proprietary isolate of reovirus Type 3 Dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase 1 – 2 trials; no clinical trials have been conducted in patients with hematologic malignancies. A phase 1 trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by In situ based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer up regulated gene 2 (CUG2) were evaluated in patient samples and MM cell lines. Neutralizing Anti-Reovirus Antibody (NARA) assay was performed weekly during cycle 1. There were no dose limiting toxicities (DLTs), patients reached the 3 x 1010 TCID50 daily on days 1-5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. In situ hybridization demonstrated reoviral genome confined in MM cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA positive cells. The longest durations of stable disease were 4, 5 and 8 months. Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within MM cells. Our data support that in MM cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.