title: Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans.
abstract: Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa-Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec-treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody-mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types.
authors.affiliation: Pusan National University and Medical Research Institute, Pusan National University, 1-10 Ami-Dong, Seo-Gu, Busan 602-739, South Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.forename: Anne
authors.initials: A
authors.lastname: Moon
authors.forename: Jeong
authors.initials: J
authors.lastname: Heo
authors.forename: Yu Kyoung
authors.initials: YK
authors.lastname: Lee
authors.forename: Mong
authors.initials: M
authors.lastname: Cho
authors.forename: Jun Woo
authors.initials: JW
authors.lastname: Lee
authors.forename: Seong-Geun
authors.initials: SG
authors.lastname: Kim
authors.forename: Dae Hwan
authors.initials: DH
authors.lastname: Kang
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Byeong Ho
authors.initials: BH
authors.lastname: Park
authors.forename: David H
authors.initials: DH
authors.lastname: Kirn
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000378:metabolism; D002470:Cell Survival; D003165:Complement System Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007167:Immunotherapy; D009336:Necrosis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D011817:Rabbits; D044967:Serum / Q000378:metabolism; D016019:Survival Analysis; D014616:Vaccinia virus / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D003165:Complement System Proteins