Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters
Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters
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DOI：
10.1002/ijc.28132
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发表时间：
2013-09-15
影响因子：
6.4
通讯作者：
Hyodo, Ichinosuke
中科院分区：
文献类型：
--
作者：
Hasegawa, Naoyuki;Abei, Masato;Hyodo, Ichinosuke
溶瘤病毒（OV）是具有巨大前景的新型癌症治疗药物，但宿主抗病毒免疫是其疗效的障碍。因此，环磷酰胺（CP）的免疫抑制作用已被证明可以增强许多OV的溶瘤功效，但其对携带治疗基因的OV的作用仍不清楚。我们以前曾报道过AxE 1CAUP的疗效，溶瘤腺病毒（OAd）表达尿嘧啶磷酸核糖转移酶（UPRT），一种酶，显着增强5-氟尿嘧啶（5-FU）的毒性，在免疫缺陷，广告nonpermissive裸鼠。在这里，我们探讨了肿瘤内（i.t.）AxE 1 CAUP/5-FU疗法及其与CP联合治疗免疫活性、Ad允许的叙利亚仓鼠中的同基因HaP-T1胰腺癌。AxE 1CAUP在HaP-T1细胞中感染、复制、表达UPRT，并增强HaP-T1细胞对5-FU的敏感性。I.T. AxE 1 CAUP/5-FU处理抑制皮下HaP-T1同种异体移植物的生长。与高剂量CP的组合抑制血清Ad中和抗体形成，增加肿瘤内AxE 1CAUP复制和UPRT表达，并导致进一步增强5-FU的治疗效果。在这些处理期间，体重和肝脏和肺的组织学均未发生变化。临床批准的中剂量CP也增强了i.t. AxE 1CAUP/5-FU治疗，这不受预先存在的对载体的免疫力的影响。这些数据证明了具有自杀基因的OAd与CP组合治疗免疫活性的Ad允许动物中的同基因肿瘤的优异抗肿瘤功效和安全性，表明CP在克服有效OV介导的基因治疗的抗病毒免疫障碍方面的功效。溶瘤病毒作为癌症治疗剂提供了很大的希望，但其功效必须克服宿主的抗病毒免疫。本研究证明了表达尿嘧啶磷酸核糖基转移酶的溶瘤腺病毒（OAd）的疗效和安全性，并通过高剂量或临床批准的安全剂量的免疫抑制剂环磷酰胺（CP）在有或没有预先存在的免疫力的叙利亚仓鼠中进一步增强了这种疗效。这是第一项研究证明了CP增强了携带治疗基因的OAd在Ad允许免疫活性动物中的功效，表明CP能够克服有效病毒基因治疗的抗病毒免疫障碍。
Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high-dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy.What's new? Oncolytic viruses offer great promise as cancer therapeutics, but host antiviral immunity must be overcome for their efficacy. This study demonstrates the efficacy and safety of an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase and further enhancement of this efficacy by a high-dose or clinically-approved safe dose of the immunosuppressive agent cyclophosphamide (CP) in Syrian hamsters with or without preexisting immunity. This is the first study demonstrating enhancement by CP of the efficacy of an OAd armed with a therapeutic gene in Ad-permissive immunocompetent animals, indicating the ability of CP to overcome the hurdle of antiviral immunity for effective virus-gene therapy.