We investigated the anticancer efficacy, blood clearance, and tissue biodistribution of systemically administered retargeted oncolytic herpes simplex viruses (ReHVs) in HSV-naïve and HSV-preimmunized (HSV-IMM) mice. Efficacy was tested against lung tumors formed upon intravenous administration of cancer cells, a model of metastatic disease, and against subcutaneous distant tumors. In naïve mice, HER2- and hPSMA-retargeted viruses, both armed with mIL-12, were highly effective, even when administered to mice with well-developed tumors. Efficacy was higher for combination regimens with immune checkpoint inhibitors. A significant amount of infectious virus persisted in the blood for at least 1 h. Viral genomes, or fragments thereof, persisted in the blood and tissues for days. Remarkably, the only sites of viral replication were the lungs of tumor-positive mice and the subcutaneous tumors. No replication was detected in other tissues, strengthening the evidence of the high cancer specificity of ReHVs, a property that renders ReHVs suitable for systemic administration. In HSV-IMM mice, ReHVs administered at late times failed to exert anticancer efficacy, and the circulating virus was rapidly inactivated. Serum stability and in vivo whole blood stability assays highlighted neutralizing antibodies as the main factor in virus inactivation. Efforts to deplete mice of the neutralizing antibodies are ongoing.
我们在未感染过HSV的小鼠与HSV预免疫小鼠中，研究了全身给药的重靶向溶瘤性单纯疱疹病毒的抗癌效果、血液清除情况及组织生物分布。通过在静脉注射癌细胞形成的肺肿瘤（转移性疾病模型）以及皮下远端肿瘤模型中测试其疗效。在未感染过HSV的小鼠中，靶向HER2和hPSMA且携带mIL-12的病毒均显示出高度有效性，即使是在肿瘤已充分发展的小鼠中给药亦然。与免疫检查点抑制剂联合使用的方案疗效更佳。感染性病毒在血液中可显著存留至少1小时，病毒基因组或其片段在血液和组织中可持续存在数日。值得注意的是，病毒复制的唯一部位是携带肿瘤小鼠的肺部及皮下肿瘤，其他组织未检测到复制，这进一步证实了重靶向溶瘤病毒的高度癌症特异性，使其适用于全身给药。在HSV预免疫小鼠中，后期给药的重靶向溶瘤病毒未能发挥抗癌效果，循环病毒被迅速灭活。血清稳定性及体内全血稳定性实验表明，中和抗体是病毒灭活的主要因素。目前正在努力清除小鼠体内的中和抗体。
肿瘤(癌症)患者之家