title: First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity.
abstract: Oncolytic viral therapy utilizes a tumor-selective replicating virus which preferentially infects and destroys cancer cells and triggers antitumor immunity. The Western Reserve strain of vaccinia virus (VV) is the most virulent strain of VV in animal models and has been engineered for tumor selectivity through two targeted gene deletions (vvDD). We performed the first-in-human phase 1, intratumoral dose escalation clinical trial of vvDD in 16 patients with advanced solid tumors. In addition to safety, we evaluated signs of vvDD replication and spread to distant tumors, pharmacokinetics and pharmacodynamics, clinical and immune responses to vvDD. Dose escalation proceeded without dose-limiting toxicities to a maximum feasible dose of 3 × 10(9) pfu. vvDD replication in tumors was reproducible. vvDD genomes and/or infectious particles were recovered from injected (n = 5 patients) and noninjected (n = 2 patients) tumors. At the two highest doses, vvDD genomes were detected acutely in blood in all patients while delayed re-emergence of vvDD genomes in blood was detected in two patients. Fifteen of 16 patients exhibited late symptoms, consistent with ongoing vvDD replication. In summary, intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Downs-Canner
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Zong Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Uma N M
authors.initials: UN
authors.lastname: Rao
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Lekshmi
authors.initials: L
authors.lastname: Ramalingam
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Thorne
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Jones
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Wieckowski
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: O'Malley
authors.affiliation: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Manijeh
authors.initials: M
authors.lastname: Daneshmand
authors.affiliation: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Kang
authors.initials: K
authors.lastname: Hu
authors.affiliation: Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: 1] Department of Pharmacology, Pusan National University, Busan, South Korea [2] SillaJen, Inc., Seoul, South Korea.
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Hwang
authors.affiliation: SillaJen, Inc., Seoul, South Korea.
authors.forename: Anne
authors.initials: A
authors.lastname: Moon
authors.affiliation: SillaJen, Inc., Seoul, South Korea.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.affiliation: SillaJen, Inc., Seoul, South Korea.
authors.forename: David H
authors.initials: DH
authors.lastname: Kirn
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
mesh_terms: D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D017353:Gene Deletion; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014616:Vaccinia virus / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics*