Novel Chimeric Immuno-Oncolytic Virus CF33-hNIS-antiPDL1 for the Treatment of Pancreatic Cancer.
Novel Chimeric Immuno-Oncolytic Virus CF33-hNIS-antiPDL1 for the Treatment of Pancreatic Cancer.
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DOI：
10.1016/j.jamcollsurg.2019.12.027
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发表时间：
2020-04
影响因子：
5.2
通讯作者：
Fong Y
中科院分区：
文献类型：
--
作者：
Woo Y;Zhang Z;Yang A;Chaurasiya S;Park AK;Lu J;Kim SI;Warner SG;Von Hoff D;Fong Y
胰导管腺癌（PDAC）引起的腹膜癌（PC）是致命的。我们的临床前研究提出了一种针对PDAC PC的有效治疗方法，采用一种新的溶瘤病毒剂CF33-hNIS-antiPDL1。CF33-hNIS- antipdl1是一种基因工程嵌合正痘病毒CF33，具有人碘化钠同体转运蛋白（hNIS）和抗pd - l1抗体（anti-PD-L1）。在不同剂量（感染多重度（multiplicity of infection， MOI） = 0.01, 0.1, 1,10）下测试了该病毒对5种PDAC细胞系的体外细胞毒能力。通过免疫印迹、免疫沉淀和PD-1/PD-L1生物测定验证病毒编码抗PD-L1抗体的产生和阻断功能。用PBS或单剂量（1x105个斑块形成单位）腹腔注射（IP）或静脉注射（IV） CF33-hNIS-antiPDL1治疗体内PC小鼠模型，无论是否存在通过向裸鼠注射AsPC-1-ffluc细胞而产生的皮下（SC）肿瘤。在肿瘤植入后的第0天、第2天或第14天对PC肿瘤小鼠进行治疗。CF33-hNIS-antiPDL1以剂量依赖性的方式杀死PDAC细胞，在第8天达到90%的细胞杀伤。感染CF33-hNIS-antiPDL1的细胞产生具有生物活性的抗PD-L1抗体，阻断PD-1/PD-L1相互作用。在体内，单剂量病毒可减轻肿瘤负荷，延长治疗小鼠的生存期。观察到IP给药CF33-hNIS-antiPDL1比静脉给药更有效。CF33-hNIS-antiPDL1病毒能有效感染和杀伤人pdac，并产生功能性抗pd - l1抗体。单剂量IP给药CF33-hNIS-antiPDL1可有效降低腹膜肿瘤负荷，提高生存率，优于静脉给药。在人类胰腺导管腺癌（PDAC）肿瘤临床前模型中，腹腔注射新型溶瘤病毒CF33-hNIS-antiPDL1可减轻肿瘤负担并延长生存期。这项研究的发现可以促进PDAC治疗胰腺癌的给药途径和治疗时机的策略。
Peritoneal carcinomatosis (PC) from pancreatic ductal adenocarcinoma (PDAC) is fatal. Our preclinical study presents an effective treatment against PDAC PC employing a novel oncolytic viral agent, CF33-hNIS-antiPDL1. CF33-hNIS-antiPDL1 is a genetically engineered chimeric orthopoxvirus, CF33, armed with the human Sodium Iodide Symporter (hNIS) and anti-PD-L1 antibody (anti-PD-L1). The in vitro cytotoxic ability of this virus against five PDAC cell lines was tested at various doses (multiplicity of infection (MOI) = 0.01, 0.1, 1, 10). Production and blockade function of virus-encoded anti-PD-L1 antibody were verified using immunoblot, immunoprecipitation, and PD-1/PD-L1 bioassay. In vivo mouse models of PC, with or without subcutaneous (SC) tumors created by injecting AsPC-1-ffluc cells into nude mice, were treated with PBS or a single dose (1x105 plaque-forming units) of either intraperitoneal (IP) or intravenous (IV) injections of CF33-hNIS-antiPDL1. Mice with PC tumors were treated on days 0, 2, or 14 following tumor implantation. CF33-hNIS-antiPDL1 killed PDAC cells in a dose-dependent manner achieving >90% cell killing by day 8. Cells infected with CF33-hNIS-antiPDL1 produced bioactive anti-PD-L1 antibody which blocked PD-1/PD-L1 interaction. In vivo, single dose of virus reduced tumor burden and prolonged survival of treated mice. It was observed that IP administration of CF33-hNIS-antiPDL1 was more effective than IV administration. CF33-hNIS-antiPDL1 virus is effective in infecting and killing human PDACs and producing functional anti-PD-L1 antibody. IP delivery of CF33-hNIS-antiPDL1 effectively reduces peritoneal tumor burden and improves survival after only one dose and is superior to IV delivery. Intraperitoneal delivery of the novel oncolytic virus CF33-hNIS-antiPDL1 reduces tumor burden and prolongs survival in preclinical models of human pancreatic ductal adenocarcinoma (PDAC) tumors. Findings from this study could advance strategies for route of delivery and timing for treatment of PDAC with pancreatic cancer.
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影响因子：
6.4
作者：
Ito, D;Fujimoto, K;Doi, R
通讯作者：
Doi, R
影响因子：
4.7
作者：
LaRocca CJ;Warner SG
通讯作者：
Warner SG
影响因子：
7.2
作者：
Priceman SJ;Gerdts EA;Tilakawardane D;Kennewick KT;Murad JP;Park AK;Jeang B;Yamaguchi Y;Yang X;Urak R;Weng L;Chang WC;Wright S;Pal S;Reiter RE;Wu AM;Brown CE;Forman SJ
通讯作者：
Forman SJ
影响因子：
5.7
作者：
Choi, Audrey H.;O'Leary, Michael P.;Chen, Nanhai G.
通讯作者：
Chen, Nanhai G.
DOI：
10.1016/j.omto.2018.03.001
发表时间：
2018-06-29
期刊：
MOLECULAR THERAPY ONCOLYTICS
影响因子：
--
作者：
O'Leary, Michael P.;Warner, Susanne G.;Chen, Nanhai G.
通讯作者：
Chen, Nanhai G.