1] Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA [2] Virology and Gene Therapy Track, Mayo Graduate School, Rochester, Minnesota, USA.
Mol Ther. 2013 Nov;21(11):2019-31. doi: 10.1038/mt.2013.171. Epub 2013 Aug 5.
We developed here a vaccine-identical measles virus (MV) as an oncolytic agent against mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin's lymphoma that is difficult to cure but radiosensitive. We armed the virus with the sodium-iodide symporter, which concentrates iodide within infected cells enabling noninvasive imaging and combination radiovirotherapy. Through high-resolution in vivo and ex vivo imaging, we visualized the spread of infections in primary and metastatic tumors for over 2 weeks after therapy, documenting homogeneous virus seeding and spread restricted to perfused tissue. Infection of metastases was more rapid and intense than primary tumors, achieving isotope uptake within about threefold the efficiency of the thyroid. Virotherapy combined with systemic (131)I resulted in more rapid disease regression than either therapy alone. In addition to ubiquitous CD46, vaccine MV retains cell entry through its immune cell-specific receptor signaling lymphocytic activation molecule (SLAM). We asked whether both receptors could sustain effective oncolysis of MCL. Strikingly, only SLAM-dependent entry sustained efficient viral spread, tumor regression, and prolonged survival. These observations shift the focus of future clinical trials to SLAM-expressing hematologic malignancies and suggest that oncolytic vectors may depend on tissue-specific receptors for both cell entry and activation of responses assisting their replication.
我们开发了一种疫苗等价麻疹病毒（MV）作为治疗套细胞淋巴瘤（MCL）的溶瘤剂，MCL 是一种侵袭性 B 细胞非霍奇金淋巴瘤，难以治愈但对放疗敏感。我们用钠碘转运体武装病毒，该转运体能使碘在感染细胞内浓缩，从而实现非侵入性成像和联合放病毒疗法。通过高分辨率的体内和离体成像，我们在治疗后超过 2 周的时间内观察到原发和转移性肿瘤感染的扩散情况，记录到均匀的病毒播种和局限于灌注组织的扩散。转移灶的感染比原发灶更快、更强烈，达到了甲状腺摄取效率的约三倍。病毒疗法与全身（131）I 联合治疗比单独治疗能更迅速地使疾病消退。除了普遍存在的 CD46 外，疫苗 MV 通过其免疫细胞特异性受体信号淋巴细胞激活分子（SLAM）保留了细胞进入能力。我们想知道这两种受体是否都能维持对 MCL 的有效溶瘤作用。令人惊讶的是，只有 SLAM 依赖性进入才能维持有效的病毒传播、肿瘤消退和延长生存。这些观察结果将未来临床试验的重点转移到表达 SLAM 的血液恶性肿瘤上，并表明溶瘤载体可能依赖于组织特异性受体来进行细胞进入和激活反应，以协助其复制。
