Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer

Jeong Heo, Tony Reid, Leyo Ruo, Caroline J. Breitbach, Steven Rose, Mark Bloomston, Mong Cho, Ho Yeong Lim, Hyun Cheol Chung, Chang Won Kim, James Burke, Riccardo Lencioni, Theresa Hickman, Anne Moon, Yeon Sook Lee, Mi Kyeong Kim, Manijeh Daneshmand, Kara Dubois, Lara Longpre, Minhtran NgoCliona Rooney, John C. Bell, Byung Geon Rhee, Richard Patt, Tae Ho Hwang, David H. Kirn

Research output: Contribution to journalArticle

397 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)329-336
Number of pages8
JournalNature Medicine
Volume19
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Heo, J., Reid, T., Ruo, L., Breitbach, C. J., Rose, S., Bloomston, M., Cho, M., Lim, H. Y., Chung, H. C., Kim, C. W., Burke, J., Lencioni, R., Hickman, T., Moon, A., Lee, Y. S., Kim, M. K., Daneshmand, M., Dubois, K., Longpre, L., ... Kirn, D. H. (2013). Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Medicine, 19(3), 329-336. https://doi.org/10.1038/nm.3089