oHSV-1-GM-CSF联合anti PD-L1抗体治疗小鼠双侧结肠癌移植瘤  

Efficacy of OHSV-1-GM-CSF Combined with Anti PD-L1 Antibody on Bilateral Colon Xenograft Cancer Tumor of Mice

作　　者：王圣润 朱程扬 朱伟 胡宗风 李劲风 李小鹏 WANG Shengrun;ZHU Chengyang;ZHU Wei;HU Zongfeng;LI Jinfeng;LI Xiaopeng(School of Pharmacy,Key Laboratory of Molecular Pharmacology and Drug Evaluation(Yantai University),Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai 264005,China)

机构地区：[1]烟台大学药学院,分子药理和药物评价教育部重点实验室(烟台大学),新型制剂与生物技术药物研究山东省高校协同创新中心,山东烟台264005

出　　处：《烟台大学学报（自然科学与工程版）》2024年第4期454-463,共10页Journal of Yantai University(Natural Science and Engineering Edition)

基　　金：山东省顶尖人才“一事一议”项目(主持人:李小鹏)。

摘　　要：为了验证oHSV-1-GM-CSF与anti PD-L1抗体联用在双侧结肠癌皮下移植瘤模型中的全身抗肿瘤活性,并初步探究该联用方案在体内的作用原理,在BALB/c小鼠上利用CT26.WT细胞建立双侧结肠癌皮下移植瘤模型并进行随机分组,设置Vehicle、oHSV-1-GM-CSF、anti PD-L1以及oHSV-1-GM-CSF+anti PD-L1组。治疗结束后,取小鼠外周血淋巴细胞进行流式细胞术和体外杀伤实验,并继续观察治疗结束后的小鼠肿瘤消退情况或消退的肿瘤重新发生的情况。结果显示,oHSV-1-GM-CSF能在CT26.WT细胞上表达mGM-CSF,且溶瘤作用与空载病毒相比无显著差异;在体内实验中oHSV-1-GM-CSF对治疗侧的肿瘤抑制效果强于空载病毒,与anti PD-L1抗体联用后产生更强的抑制全身肿瘤的作用;流式结果显示,联用组小鼠外周血和脾脏中与特异性免疫相关的细胞比例显著上调,且外周血淋巴细胞能在体外特异性杀伤CT26.WT细胞而对同种属的4T1细胞无明显作用;生存期结果显示联用组能显著延长小鼠生存期,存活率为33.3%,且无肿瘤重新发生的情况。综上所述,oHSV-1-GM-CSF与anti PD-L1抗体联用后能加强机体的特异性免疫从而产生持久的抑瘤效果,并延长小鼠生存期,为临床对结肠癌的治疗方案提供数据支持。In order to verify the effectiveness of oHSV-1-GM-CSF combined with anti-PD-L1 antibody in treating bilateral colon cancer,a subcutaneous tumor model is set up using CT26.WT cells in BALB/c mice.Tumor-bearing mice are randomly assigned to four groups:Vehicle,oHSV-1-GM-CSF,anti-PD-L1,and oHSV-1-GM-CSF+anti-PD-L1.After administration,blood lymphocytes are taken from the mice and analyzed,and tumor regression or recurrence is also observed.The results show that oHSV-1-GM-CSF can express mGM-CSF on CT26.WT cells and there is no significant difference in oncolytic effect between oHSV-1-GM-CSF and the unload virus.In vivo experiments show that,oHSV-1-GM-CSF has a more substantial tumor inhibition effect than the no-load virus on the drug administration side,and oHSV-1-GM-CSF combined with anti-PD-L1 antibody produces a more substantial tumor inhibition effect on the whole body.The proportion of specific immune-related cells in peripheral blood and spleen of the combined treatment group significantly increases.Peripheral blood lymphocytes can kill CT26.WT cells in vitro,meanwhile has no effect on 4T1 cells of the same species.The combined treatment group significantly prolongs the survival time of mice,with a survival rate of 33.3%,and tumor recurrence doesn’t occur.In conclusion,the combination of oHSV-1-GM-CSF and anti-PD-L1 antibody can enhance the specific immunity of the body,produce a lasting tumor inhibition effect,prolong the survival of mice,and provide data support for clinical treatment of colon cancer.

关 键 词：结肠癌 双侧结肠癌移植瘤 溶瘤病毒 特异性免疫 

分 类 号：R735.3+5[医药卫生—肿瘤]