title: Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer.
abstract: Oncolytic viruses and active immunotherapeutics have complementary mechanisms of action (MOA) that are both self amplifying in tumors, yet the impact of dose on subject outcome is unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic vaccinia virus. To determine the optimal JX-594 dose in subjects with advanced hepatocellular carcinoma (HCC), we conducted a randomized phase 2 dose-finding trial (n=30). Radiologists infused low- or high-dose JX-594 into liver tumors (days 1, 15 and 29); infusions resulted in acute detectable intravascular JX-594 genomes. Objective intrahepatic Modified Response Evaluation Criteria in Solid Tumors (mRECIST) (15%) and Choi (62%) response rates and intrahepatic disease control (50%) were equivalent in injected and distant noninjected tumors at both doses. JX-594 replication and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression preceded the induction of anticancer immunity. In contrast to tumor response rate and immune endpoints, subject survival duration was significantly related to dose (median survival of 14.1 months compared to 6.7 months on the high and low dose, respectively; hazard ratio 0.39; P=0.020). JX-594 demonstrated oncolytic and immunotherapy MOA, tumor responses and dose-related survival in individuals with HCC.
authors: Department of Internal Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Seo-Gu, Busan, South Korea.
authors: Jeong
authors: J
authors: Heo
authors: Tony
authors: T
authors: Reid
authors: Leyo
authors: L
authors: Ruo
authors: Caroline J
authors: CJ
authors: Breitbach
authors: Steven
authors: S
authors: Rose
authors: Mark
authors: M
authors: Bloomston
authors: Mong
authors: M
authors: Cho
authors: Ho Yeong
authors: HY
authors: Lim
authors: Hyun Cheol
authors: HC
authors: Chung
authors: Chang Won
authors: CW
authors: Kim
authors: James
authors: J
authors: Burke
authors: Riccardo
authors: R
authors: Lencioni
authors: Theresa
authors: T
authors: Hickman
authors: Anne
authors: A
authors: Moon
authors: Yeon Sook
authors: YS
authors: Lee
authors: Mi Kyeong
authors: MK
authors: Kim
authors: Manijeh
authors: M
authors: Daneshmand
authors: Kara
authors: K
authors: Dubois
authors: Lara
authors: L
authors: Longpre
authors: Minhtran
authors: M
authors: Ngo
authors: Cliona
authors: C
authors: Rooney
authors: John C
authors: JC
authors: Bell
authors: Byung-Geon
authors: BG
authors: Rhee
authors: Richard
authors: R
authors: Patt
authors: Tae-Ho
authors: TH
authors: Hwang
authors: David H
authors: DH
authors: Kirn
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000378:metabolism; D015996:Survival Rate; D014616:Vaccinia virus / Q000235:genetics* / Q000502:physiology; D014779:Virus Replication
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor
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