肿瘤细胞治疗研究
英文原题：Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy.
我们构建了一种针对GBM免疫治疗的重新靶向、安全且可追踪的溶瘤病毒，具有强大的细胞毒性和免疫刺激活性。
胶质母细胞瘤（GBM）是一种侵袭性强、对免疫治疗耐药的大脑肿瘤。在此，我们基于单纯疱疹病毒1型设计了一种用于GBM病毒免疫治疗的溶瘤病毒平台。我们对高致细胞病变的MacIntyre株进行突变，以增加其扩散能力和溶瘤活性、限制遗传漂变、防止神经元感染并实现PET示踪。我们整合了microRNA靶向盒以减弱其在健康脑细胞中的复制。此外，我们对gD包膜蛋白进行工程改造，利用EGFR特异性或整合素特异性结合分子使其特异性靶向GBM。最后，我们整合了五种免疫调节因子，通过局部表达IL-12、anti-PD1、一种双特异性T细胞衔接器、15-羟基前列腺素脱氢酶和anti-TREM2来重塑肿瘤微环境（TME），以靶向GBM TME中的T细胞和髓系细胞。单次瘤内注射提高了GBM临床前模型中的生存率，同时促进了TME中肿瘤特异性T细胞、NK 细胞和髓系细胞的应答。总之，我们工程化了一种重新靶向的、安全且可示踪的溶瘤病毒，其具有强细胞毒性和免疫刺激活性，可用于GBM免疫治疗。
Glioblastoma (GBM) is an aggressive, immunotherapy-resistant brain tumor. Here, we engineered an oncolytic virus platform based on herpes simplex virus 1 for GBM viroimmunotherapy. We mutated the highly cytopathic MacIntyre strain to increase spread and oncolytic activity, limit genetic drift, prevent neuron infection and enable PET tracing. We incorporated microRNA target cassettes to attenuate replication in healthy brain cells. Moreover, we engineered the gD envelope protein to specifically target GBM using EGFR-specific or integrin-specific binders. Lastly, we incorporated five immunomodulators to remodel the tumor microenvironment (TME) by locally expressing IL-12, anti-PD1, a bispecific T cell engager, 15-hydroxyprostaglandin dehydrogenase and anti-TREM2 to target T cells and myeloid cells in the GBM TME. A single intratumoral injection increased survival in GBM preclinical models, while promoting tumor-specific T cell, natural killer cell and myeloid cell responses in the TME. In summary, we engineered a retargeted, safe and traceable oncolytic virus with strong cytotoxic and immunostimulatory activities for GBM immunotherapy.
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