title: Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters.
abstract: 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.
authors: Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors: Naoyuki
authors: N
authors: Hasegawa
authors: Masato
authors: M
authors: Abei
authors: Kazunari K
authors: KK
authors: Yokoyama
authors: Kuniaki
authors: K
authors: Fukuda
authors: Emiko
authors: E
authors: Seo
authors: Rei
authors: R
authors: Kawashima
authors: Yuri
authors: Y
authors: Nakano
authors: Takeshi
authors: T
authors: Yamada
authors: Koji
authors: K
authors: Nakade
authors: Hirofumi
authors: H
authors: Hamada
authors: Yuichi
authors: Y
authors: Obata
authors: Ichinosuke
authors: I
authors: Hyodo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006224:Cricetinae; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D007121:Immunocompetence; D008647:Mesocricetus; D050504:Oncolytic Viruses / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000628:therapy*; D010430:Pentosyltransferases / Q000235:genetics*; D014161:Transduction, Genetic
chemical_list: D003520:Cyclophosphamide; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D005472:Fluorouracil
keywords: conditionally replicative adenovirus; gene therapy; immunosuppression; oncolytic virus; pancreas cancer