Pharmacokinetic enhancement of oncolytic virus M1 by inhibiting JAK-STAT pathway  

作　　者：Jingyi Tan Jiayu Zhang Cheng Hu Gongwei Wang Qianyao Ren Chaoqun Wang Jia Dan Zexin Zeng Jun Hu Wenbo Zhu Jiankai Liang Jing Cai Ying Liu Guangmei Yan Yuan Lin 

机构地区：[1]Department of Pharmacology,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou 510080,China [2]The Sixth Affiliated Hospital,Sun Yat-sen University,Guangzhou 510655,China [3]Department of Urology,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China [4]Advanced Medical Technology Center,the First Affiliated Hospital-Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou 510080,China [5]Key Laboratory of Human Microbiome and Elderly Chronic Diseases,Ministry of Education,Guangzhou 510655,China [6]Department of Infectious Diseases,the Third Affiliated Hospital of Sun Yat-sen University,Guangzhou 510630,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2554-2566,共13页药学学报（英文版）

基　　金：supported by National Key R&D Program of China(No.2021YFA0909800,China);Guangdong Basic and Applied Basic Research Foundation(Nos.2022B1515020056,2021A1515011881,2023A1515010737,China);Leading team for entrepreneurship in Guangzhou,Guangdong Province(No.201809020004,China);Fundamental Research Funds for the Central Universities(No.22ykqb12,China);Pioneering talents project of Guangzhou Development Zone,Guangdong Province(2020-L036,China);Natural Science Foundation of Guangdong Province(No.2022A1515011056,China).

摘　　要：Oncolytic viruses(OVs),a group of replication-competent viruses that can selectively infect and kill cancer cells while leaving healthy cells intact,are emerging as promising living anticancer agents.Unlike traditional drugs composed of non-replicating compounds or biomolecules,the replicative nature of viruses confer unique pharmacokinetic properties that require further studies.Despite some pharmacokinetics studies of OVs,mechanistic insights into the connection between OV pharmacokinetics and antitumor efficacy remain vague.Here,we characterized the pharmacokinetic profile of oncolytic virus M1(OVM)in immunocompetent mouse tumor models and identified the JAK-STAT pathway as a key modulator of OVM pharmacokinetics.By suppressing the JAK-STAT pathway,early OVM pharmacokinetics are ameliorated,leading to enhanced tumor-specific viral accumulation,increased AUC and Cmax,and improved antitumor efficacy.Rather than compromising antitumor immunity after JAK-STAT inhibition,the improved pharmacokinetics of OVM promotes T cell recruitment and activation in the tumor microenvironment,providing an optimal opportunity for the therapeutic outcome of immune checkpoint blockade,such as anti-PD-L1.Taken together,this study advances our understanding of the pharmacokinetic-pharmacodynamic relationship in OV therapy.

关 键 词：PHARMACOKINETICS Oncolytic virus JAK-STAT ANTICANCER 

分 类 号：R96[医药卫生—药理学]