Department of Hematology, University College London, London, United Kingdom;
Blood. 2014 Feb 27;123(9):1327-35. doi: 10.1182/blood-2013-09-528851. Epub 2013 Dec 17.
Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL.
溶瘤性减毒麻疹病毒（MV）的临床试验正在进行中，但在免疫个体中成功进行全身递送仍然是一个主要挑战。我们在 16 例接受包括多种免疫抑制药物在内的治疗的急性淋巴细胞白血病（ALL）成人患者中发现了高水平的抗-MV 抗体。为了解决这一挑战，我们使用人骨髓间充质基质细胞（BM-MSCs）在 B 细胞前体 ALL 的系统性异种移植模型中有效地递送 MV。BM-MSCs 可以成功地进行 MV 的体外加载，并且可以在没有毒性的情况下在细胞内扩增 MV。活细胞共聚焦成像显示，在抗体存在的情况下，BM-MSCs 和 ALL 靶细胞之间存在病毒传递。在播散性 ALL 的小鼠模型中，高滴度人抗-MV 抗体的被动免疫完全阻断了成功的 MV 治疗（通过生物发光定量和存活判断）。重要的是，在接受 BM-MSCs 递送的 MV 的免疫小鼠中没有观察到这种阻断。这些数据支持在 ALL 患者中使用 BM-MSCs 作为 MV 的细胞载体。
