title: Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers.
abstract: We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Downs-Canner
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Zong Sheng
authors.initials: ZS
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Roshni
authors.initials: R
authors.lastname: Ravindranathan
authors.affiliation: SillaJen Biotherapeutics Inc., San Francisco, CA, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: O'Malley
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Jones
authors.affiliation: SillaJen Biotherapeutics Inc., San Francisco, CA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Moon
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Judith Andrea
authors.initials: JA
authors.lastname: McCart
authors.affiliation: Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Herbert J
authors.initials: HJ
authors.lastname: Zeh
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000276:immunology; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics* / Q000493:pharmacokinetics; D006801:Humans; D018836:Inflammation Mediators; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology; D011212:Poxviridae / Q000235:genetics* / Q000276:immunology; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D018836:Inflammation Mediators