Thirukkumaran C M, Shi Z Q, Luider J, Kopciuk K, Bahlis N, Neri P, Pho M, Stewart D, Mansoor A, Morris D G
1] Department of Oncology, University of Calgary, Calgary, Alberta, Canada [2] Department of Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada.
Department of Oncology, Tom Baker Cancer Center, Calgary, Alberta, Canada.
Bone Marrow Transplant. 2014 Jan;49(1):80-6. doi: 10.1038/bmt.2013.130. Epub 2013 Aug 26.
Autologous stem cell rescue (ASCT) following high-dose myeloablative chemotherapy is considered to be a therapeutic option for many multiple myeloma (MM) patients; however relapse post ASCT presents a major challenge. The oncolytic potential of reovirus has been previously demonstrated and is currently undergoing phase I monotherapy clinical trials for MM and phase II/III clinical trials for solid tumors. Here we tested the hypothesis that reovirus can successfully purge MM in a murine model that partially recapitulates human MM. RPMI 8226, MM1S, H929 and U266 human myeloma cell lines were exposed to reovirus and oncolysis was assessed. Apheresis product admixed with MM cells was purged with live reovirus (LV) or dead virus (DV) and purging efficacy was monitored via flow cytometry, reverse transcribed-PCR (RT-PCR) and disease relapse in non obese diabetic/severe combined immune deficient (NOD/SCID) mice. Significant LV purging was seen with MM1S, H929 and U266 and the complete ex vivo purging achieved with RPMI 8226 was confirmed by flow cytometry, RT-PCR and absence of disease relapse in vivo. Mice that received LV-purged autografts exhibited 100% survival in comparison to mice that received DV-purged controls. Reovirus's unique ability to kill MM while sparing hematopoietic stem cells places it as an attractive purging agent for MM during ASCT.
大剂量清髓性化疗后的自体干细胞挽救（ASCT）被认为是许多多发性骨髓瘤（MM）患者的一种治疗选择；然而，ASCT后的复发是一个重大挑战。呼肠孤病毒的溶瘤潜力此前已得到证实，目前正在进行MM的I期单药临床试验以及实体瘤的II/III期临床试验。在此，我们在一个部分模拟人类MM的小鼠模型中测试了呼肠孤病毒能否成功清除MM的假设。将RPMI 8226、MM1S、H929和U266人骨髓瘤细胞系暴露于呼肠孤病毒，并评估溶瘤情况。用活呼肠孤病毒（LV）或死病毒（DV）清除与MM细胞混合的单采产品，并通过流式细胞术、逆转录PCR（RT-PCR）以及非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠的疾病复发情况监测清除效果。在MM1S、H929和U266细胞系中观察到显著的LV清除效果，并且通过流式细胞术、RT-PCR以及体内无疾病复发证实了RPMI 8226细胞系实现了完全的体外清除。与接受DV清除对照的小鼠相比，接受LV清除自体移植物的小鼠存活率为100%。呼肠孤病毒在杀死MM细胞的同时能使造血干细胞免受损伤，这一独特能力使其成为ASCT期间MM有吸引力的清除剂。
