title: Efficacy and safety of the oncolytic herpes simplex virus rRp450 alone and combined with cyclophosphamide.
abstract: Oncolytic herpes simplex virus (oHSV) mutants are under development as anticancer therapeutics. One such vector, rRp450, is ICP6-deleted and expresses a prodrug enzyme for cyclophosphamide (CPA) (rat CYP2B1). Little is known about rRp450's toxicity profile, especially in combination with CPA. We tested rRp450/CPA for antitumor efficacy in an aggressive human xenograft sarcoma model, measured virus production in primary cells, and tested rRp450/CPA for safety in immunocompetent mice. CPA enhanced the antitumor efficacy of rRp450. Relative to wild-type HSV-1, rRp450 replication was attenuated approximately 10,000-fold in human primary hepatocytes, differentiated primary foreskin keratinocytes, and primary Schwann cells. In vivo, intravenous and intracranial (IC) rRp450 injection at the strength of 10(8) plaque-forming units (pfu) alone or followed 24 hours later by intraperitoneal (IP) CPA was well tolerated and had no significant effect clinically on blood counts or chemistries. By contrast, intravenous KOS was found to be uniformly neurotoxic at 10(5) and fatal at 10(6) pfu, and IC virus was fatal in most mice at 10(4) pfu. Low levels of virus DNA were detected in some organs following intravenous and IC virus injection, but were not significantly altered by CPA. HSV replication was not detected in reactivation studies of isolated organs. Our findings suggest rRp450/CPA is safe and warrants further study as a potential combination in anticancer therapeutics.
authors.affiliation: Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Currier
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gillespie
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Sawtell
authors.forename: Yonatan Y
authors.initials: YY
authors.lastname: Mahller
authors.forename: Greg
authors.initials: G
authors.lastname: Stroup
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Collins
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kambara
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Cripe
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003131:Combined Modality Therapy / Q000379:methods*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004279:DNA, Viral / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D012449:Safety; D012509:Sarcoma / Q000235:genetics / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics*; D013997:Time Factors
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004279:DNA, Viral; D003520:Cyclophosphamide