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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kaufman, H.L. et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 17, 718–730 (2010).
Kirn, D., Martuza, R.L. & Zwiebel, J. Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat. Med. 7, 781–787 (2001).
Liu, T.C., Galanis, E. & Kirn, D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. Nat. Clin. Pract. Oncol. 4, 101–117 (2007).
Chiocca, E.A. Oncolytic viruses. Nat. Rev. Cancer 2, 938–950 (2002).
Heise, C. & Kirn, D.H. Replication-selective adenoviruses as oncolytic agents. J. Clin. Invest. 105, 847–851 (2000).
Kirn, D.H. & Thorne, S.H. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat. Rev. Cancer 9, 64–71 (2009).
Kim, J.H. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–370 (2006).
Parato, K.A. et al. The oncolytic poxvirus JX-594 selectively replicates in and destroys cancer cells driven by genetic pathways commonly activated in cancers. Mol. Ther. 20, 749–758 (2012).
Hwang, T.H. et al. A mechanistic proof-of-concept clinical trial with JX-594, a targeted multi-mechanistic oncolytic poxvirus, in patients with metastatic melanoma. Mol. Ther. 19, 1913–1922 (2011).
Heo, J. et al. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy. Mol. Ther. 19, 1170–1179 (2011).
Thorne, S.H. et al. Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. J. Clin. Invest. 117, 3350–3358 (2007).
Wein, L.M., Wu, J.T. & Kirn, D.H. Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery. Cancer Res. 63, 1317–1324 (2003).
Senzer, N.N. et al. Phase II clinical trial of a granulocyte-macrophage colony-stimulating factor–encoding, second-generation oncolytic herpesvirus in patients with unresectable metastatic melanoma. J. Clin. Oncol. 27, 5763–5771 (2009).
Park, B.H. et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 9, 533–542 (2008).
Breitbach, C.J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).
Lencioni, R. & Llovet, J.M. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin. Liver Dis. 30, 52–60 (2010).
Liu, T.C., Hwang, T., Park, B.H., Bell, J. & Kirn, D.H. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol. Ther. 16, 1637–1642 (2008).
Choi, H. et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J. Clin. Oncol. 25, 1753–1759 (2007).
Llovet, J.M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
Cheng, A.L. et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10, 25–34 (2009).
Faivre, S. et al. Changes in tumor density in patients with advanced hepato-cellular carcinoma treated with sunitinib. Clin. Cancer Res. 17, 4504–4512 (2011).
Edeline, J. et al. Comparison of tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST in patients treated with sorafenib for hepatocellular carcinoma. Cancer 118, 147–156 (2012).
Kulesh, D.A. et al. Smallpox and pan-orthopox virus detection by real-time 3′-minor groove binder TaqMan assays on the roche LightCycler and the Cepheid smart Cycler platforms. J. Clin. Microbiol. 42, 601–609 (2004).
Choi, H. et al. CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate treatment: a quantitative analysis correlated with FDG PET findings. AJR Am. J. Roentgenol. 183, 1619–1628 (2004).
Gerdemann, U. et al. Rapidly generated multivirus-specific cytotoxic T lymphocytes for the prophylaxis and treatment of viral infections. Mol. Ther. 20, 1622–1632 (2012).
Kaplan, E.L. & Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 471–481 (1958).
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.
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.
About this article
Cite this article
Heo, J., Reid, T., Ruo, L. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 19, 329–336 (2013). https://doi.org/10.1038/nm.3089
Quantitative Proteome Responses to Oncolytic Reovirus in GM-CSF- and M-CSF-Differentiated Bone Marrow-Derived Cells
Journal of Proteome Research (2020)
Neural Stem Cells Improve the Delivery of Oncolytic Chimeric Orthopoxvirus in a Metastatic Ovarian Cancer Model
Molecular Therapy - Oncolytics (2020)
Engineering and Characterization of Oncolytic Vaccinia Virus Expressing Truncated Herpes Simplex Virus Thymidine Kinase
Frontiers of Medicine (2020)
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer (2020)