title: Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.
abstract: JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.
authors.affiliation: Pusan National University, Busan, South Korea.
authors.forename: Jeong
authors.initials: J
authors.lastname: Heo
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Breitbach
authors.forename: Anne
authors.initials: A
authors.lastname: Moon
authors.forename: Chang Won
authors.initials: CW
authors.lastname: Kim
authors.forename: Rick
authors.initials: R
authors.lastname: Patt
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Kim
authors.forename: Yu Kyung
authors.initials: YK
authors.lastname: Lee
authors.forename: Sung Yong
authors.initials: SY
authors.lastname: Oh
authors.forename: Hyun Young
authors.initials: HY
authors.lastname: Woo
authors.forename: Kelley
authors.initials: K
authors.lastname: Parato
authors.forename: Julia
authors.initials: J
authors.lastname: Rintoul
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.forename: Theresa
authors.initials: T
authors.lastname: Hickman
authors.forename: Byung-Geon
authors.initials: BG
authors.lastname: Rhee
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: David H
authors.initials: DH
authors.lastname: Kirn
authors.forename: Tae-Ho
authors.initials: TH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000628:therapy; D008545:Melanoma / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives; D050130:Oncolytic Virotherapy / Q000379:methods; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib