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.

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J.-M. Limacher, M. Homerin, B.M. Bastien and M. Lusky (all from Transgene SA) gave insightful comments on the manuscript. T.-H.H. and M.K.K. were supported by a grant of the Korea Healthcare technology Research and Development Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A091047). C.R. was supported by a pilot grant from the Dan Duncan Cancer Center. M.N. was supported by the Robert and Janice McNair Foundation and Baylor Research Advocates for Student Scientists Fund. J.C.B. is supported by the Ontario Institute for Cancer Research and the Terry Fox Foundation. Funding was provided by Jennerex, Transgene SA (Illkirch, France) and the Green Cross Corporation; grants to T.-H.H. from Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea; to J.C.B. from the Terry Fox Foundation and the Canadian Institute for Health Research (CIHR); and a pilot grant to C.R. from the Dan Duncan Cancer Center. This trial was registered with ClinicalTrials.gov, number NCT00554372.

Author information

Author notes

    • Jeong Heo
    •  & Tony Reid

    These authors contributed equally to this work.

    • Tae-Ho Hwang
    •  & David H Kirn

    These authors jointly directed this work.


  1. Department of Internal Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Seo-Gu, Busan, South Korea.

    • Jeong Heo
    • , Mong Cho
    •  & Chang Won Kim
  2. Moores Cancer Center, University of California San Diego (UCSD), La Jolla, California, USA.

    • Tony Reid
    •  & Steven Rose
  3. Department of Surgery, McMaster University Medical Centre, Hamilton, Ontario, Canada.

    • Leyo Ruo
  4. Jennerex Inc., San Francisco, California, USA.

    • Caroline J Breitbach
    • , James Burke
    • , Theresa Hickman
    • , Anne Moon
    • , Kara Dubois
    • , Lara Longpre
    • , John C Bell
    •  & David H Kirn
  5. Department of Surgery, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

    • Mark Bloomston
  6. Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Ilwon-Dong, Gang Nam-Gu, Seoul, South Korea.

    • Ho Yeong Lim
  7. Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-gu, Yongdong Severance Hospital, Seoul, South Korea.

    • Hyun Cheol Chung
  8. Division of Diagnostic Imaging and Intervention, Pisa University School of Medicine, Lungarno Pacinotti, Pisa, Italy.

    • Riccardo Lencioni
  9. SillaJen Inc., GeumJung-Gu, Busan, South Korea.

    • Yeon Sook Lee
    • , Mi Kyeong Kim
    •  & Tae-Ho Hwang
  10. Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

    • Manijeh Daneshmand
    •  & John C Bell
  11. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.

    • Minhtran Ngo
    •  & Cliona Rooney
  12. Baylor College of Medicine, Houston, Texas, USA.

    • Minhtran Ngo
    •  & Cliona Rooney
  13. Texas Children's Hospital, Houston, Texas, USA.

    • Cliona Rooney
  14. Green Cross Corporation, Giheung-gu, Yongin, South Korea.

    • Byung-Geon Rhee
  15. RadMD, Doylestown, Pennsylvania, USA.

    • Richard Patt
  16. Department of Pharmacology, Pusan National University, Busan, South Korea.

    • Tae-Ho Hwang


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D.H.K. and R.P. designed the study. C.J.B., D.H.K., T.-H.H., A.M., R.P., T.H., K.D., J.C.B., R.L., L.L., B.-G.R., M.C., C.R. and J.B. analyzed the data and wrote the manuscript. Y.S.L., M.K.K., M.D. and M.N. performed bioanalytical analyses. J.H., T.R., L.R., S.R., M.B., H.Y.L., H.C.C. and C.W.K. enrolled and managed the patients. C.J.B. and D.H.K. had access to all the data in the trial. D.H.K. made the final decision to submit for publication.

Competing interests

C.J.B., J.C.B., A.M., K.D., L.L. and D.H.K. are employees of Jennerex, Inc. R.L., M.D., R.P., J.C.B. and T.-H.H. consult for Jennerex, Inc. J.H. and M.C. have received travel grants from Jennerex, Inc. B.-G.R. is an employee of Green Cross, Inc.

Corresponding authors

Correspondence to Tae-Ho Hwang or David H Kirn.

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