Leoni Valerio, Gatta Valentina, Palladini Arianna, Nicoletti Giordano, Ranieri Dario, Dall'Ora Massimiliano, Grosso Valentina, Rossi Martina, Alviano Francesco, Bonsi Laura, Nanni Patrizia, Lollini Pier-Luigi, Campadelli-Fiume Gabriella
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
Oncotarget. 2015 Oct 27;6(33):34774-87. doi: 10.18632/oncotarget.5793.
Fully retargeted oncolytic herpes simplex viruses (o-HSVs) gain cancer-specificity from redirection of tropism to cancer-specific receptors, and are non-attenuated. To overcome the hurdles of systemic delivery, and enable oncolytic viruses (o-viruses) to reach metastatic sites, carrier cells are being exploited. Mesenchymal stromal cells (MSCs) were never tested as carriers of retargeted o-viruses, given their scarse-null expression of the cancer-specific receptors. We report that MSCs from different sources can be forcedly infected with a HER2-retargeted oncolytic HSV. Progeny virus spread from MSCs to cancer cells in vitro and in vivo. We evaluated the organ distribution and therapeutic efficacy in two murine models of metastatic cancers, following a single i.v. injection of infected MSCs. As expected, the highest concentration of carrier-cells and of viral genomes was in the lungs. Viral genomes persisted throughout the body for at least two days. The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment significantly inhibited also breast cancer metastases to the brain in NSG mice, and reduced by more than one-half the metastatic burden in the brain.
完全重新靶向的溶瘤单纯疱疹病毒（o-HSVs）通过将嗜性重定向至癌症特异性受体而获得癌症特异性，并且未减毒。为了克服全身递送的障碍，并使溶瘤病毒（o-病毒）能够到达转移部位，正在开发载体细胞。间充质基质细胞（MSCs）从未被测试作为重新靶向的o-病毒的载体，因为它们几乎不表达癌症特异性受体。我们报告不同来源的MSCs可以被一种HER2重新靶向的溶瘤HSV强制感染。子代病毒在体外和体内从MSCs传播到癌细胞。在单次静脉注射感染的MSCs后，我们评估了两种转移性癌症小鼠模型中的器官分布和治疗效果。正如预期的那样，载体细胞和病毒基因组的最高浓度在肺部。病毒基因组在全身持续存在至少两天。裸鼠中卵巢癌肺转移的生长受到强烈抑制，大多数接受治疗的小鼠似乎没有转移。该治疗还显著抑制了NSG小鼠中乳腺癌向脑的转移，并将脑中的转移负担降低了一半以上。
