Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy
Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy
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DOI：
10.1093/jnci/dju090
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发表时间：
2014-06-01
影响因子：
10.3
通讯作者：
Shah, Khalid
中科院分区：
文献类型：
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作者：
Duebgen, Matthias;Martinez-Quintanilla, Jordi;Shah, Khalid
背景 恶性多形性胶质母细胞瘤（GBM）目前的治疗方案是肿瘤切除，然后进行化疗和放射治疗。尽管溶瘤单纯疱疹病毒（oHSV）在GBM的临床试验中已被证明是安全的，但其疗效并不理想，主要是因为肿瘤切除后病毒扩散不足。方法将oHSV（MSC-oHSV）负载到人间充质干细胞（MSC）中，通过体外和体内实时成像来探索它们的命运。使用新型诊断武装oHSV突变体和实时多模态成像，在不同的小鼠GBM模型中测试了MSC-oHSV及其促凋亡变体oHSV-TRAIL封装在生物相容性合成细胞外基质（sECM）中的功效，这更准确地反映了当前恶性、耐药和切除肿瘤的临床情况。所有统计检验都是双向的。结果MSC-oHSV 有效地产生oHSV 后代，这导致oHSV 感染和肿瘤破坏的动态过程介导的体外和体内杀伤GBM。在 GBM 切除的临床前模型中，与直接注射纯化的 oHSV 相比，sECM 封装的 MSC-oHSV 导致抗 GBM 功效显着增加，从而延长了小鼠的中位生存期（Gehan-Breslow-Wilcoxin 试验 P < .001）。为了取代耐药肿瘤，负载 oHSV-TRAIL 的 MSC 在体外有效诱导具有 oHSV 和 TRAIL 耐药性 GBM 的小鼠发生细胞凋亡介导的杀伤并延长中位生存期（使用 chi(2) 应急试验，P < 0.001）。 结论 负载不同 oHSV 变体的人 MSC 提供了一个平台，可将溶瘤病毒疗法应用于切除后广泛的 GBM 中的临床，也可能对不同的癌症类型产生直接影响。
Background The current treatment regimen for malignant glioblastoma multiforme (GBM) is tumor resection followed by chemotherapy and radiation therapy. Despite the proven safety of oncolytic herpes simplex virus (oHSV) in clinical trials for GBMs, its efficacy is suboptimal mainly because of insufficient viral spread after tumor resection.Methods Human mesenchymal stem cells (MSC) were loaded with oHSV (MSC-oHSV), and their fate was explored by real-time imaging in vitro and in vivo. Using novel diagnostic and armed oHSV mutants and real-time multimodality imaging, the efficacy of MSC-oHSV and its proapoptotic variant, oHSV-TRAIL encapsulated in biocompatible synthetic extracellular matrix (sECM), was tested in different mouse GBM models, which more accurately reflect the current clinical settings of malignant, resistant, and resected tumors. All statistical tests were two-sided.Results MSC-oHSVs effectively produce oHSV progeny, which results in killing of GBMs in vitro and in vivo mediated by a dynamic process of oHSV infection and tumor destruction. sECM-encapsulated MSC-oHSVs result in statistically significant increased anti-GBM efficacy compared with direct injection of purified oHSV in a preclinical model of GBM resection, resulting in prolonged median survival in mice (P < .001 with Gehan-Breslow-Wilcoxin test). To supersede resistant tumors, MSC loaded with oHSV-TRAIL effectively induce apoptosis-mediated killing and prolonged median survival in mice bearing oHSV- and TRAIL-resistant GBM in vitro (P < .001 with chi(2) contingency test).Conclusions Human MSC loaded with different oHSV variants provide a platform to translate oncolytic virus therapies to clinics in a broad spectrum of GBMs after resection and could also have direct implications in different cancer types.