Suryawanshi Yogesh R, Nace Rebecca A, Russell Stephen J, Schulze Autumn J
Department of Molecular Medicine, Mayo Clinic College of Medicine, 200 1 Street S.W., Rochester, MN 55905, USA.
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
Mol Ther Oncolytics. 2021 Aug 25;23:1-13. doi: 10.1016/j.omto.2021.08.011. eCollection 2021 Dec 17.
A dual microRNA-detargeted oncolytic Mengovirus, vMCNC, proved highly effective against a murine plasmacytoma in an immunocompetent syngeneic mouse model; however, there remains the concern of escape mutant development and the potential for toxicity in severely immunocompromised cancer patients when it is used as an oncolytic virus. Therefore, we sought to compare the safety and efficacy profiles of an attenuated Mengovirus containing a virulence gene deletion versus vMCNC in an immunodeficient xenograft mouse model of human glioblastoma. A Mengovirus construct, vMCΔL, wherein the gene coding for the leader protein, a virulence factor, was deleted, was used for comparison. The vMCΔL induced significant levels of toxicity following treatment of subcutaneous human glioblastoma (U87-MG) xenografts as well as when injected intracranially in athymic nude mice, reducing the overall survival. The toxicity of vMCΔL was associated with viral replication in nervous and cardiac tissue. In contrast, microRNA-detargeted vMCNC demonstrated excellent efficacy against U87-MG subcutaneous xenografts and improved overall survival significantly compared to that of control mice without toxicity. These results reinforce microRNA-detargeting as an effective strategy for ameliorating unwanted toxicities of oncolytic picornaviruses and substantiate vMCNC as an ideal candidate for clinical development against certain cancers in both immunocompetent and immunodeficient hosts.
一种双重微小RNA脱靶的溶瘤脑心肌炎病毒，即vMCNC，在具有免疫活性的同基因小鼠模型中被证明对鼠浆细胞瘤高度有效；然而，当它被用作溶瘤病毒时，仍然存在逃逸突变体产生的担忧以及在严重免疫受损的癌症患者中产生毒性的可能性。因此，我们试图在人胶质母细胞瘤的免疫缺陷异种移植小鼠模型中比较含有毒力基因缺失的减毒脑心肌炎病毒与vMCNC的安全性和有效性。使用一种脑心肌炎病毒构建体vMCΔL进行比较，其中编码前导蛋白（一种毒力因子）的基因被删除。vMCΔL在皮下接种人胶质母细胞瘤（U87-MG）异种移植瘤后进行治疗时，以及在无胸腺裸鼠颅内注射时，均诱导了显著水平的毒性，降低了总体生存率。vMCΔL的毒性与神经和心脏组织中的病毒复制有关。相比之下，微小RNA脱靶的vMCNC对U87-MG皮下异种移植瘤显示出优异的疗效，与对照小鼠相比显著提高了总体生存率，且没有毒性。这些结果强化了微小RNA脱靶作为改善溶瘤微小核糖核酸病毒不良毒性的有效策略，并证实vMCNC是在免疫活性和免疫缺陷宿主中针对某些癌症进行临床开发的理想候选者。
