期刊
NATURE MEDICINE
卷 19, 期 3, 页码 329-336出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3089
关键词
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资金
- Korea Healthcare technology Research and Development Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea [A091047]
- Dan Duncan Cancer Center
- Robert and Janice McNair Foundation
- Baylor Research Advocates for Student Scientists Fund
- Ontario Institute for Cancer Research
- Terry Fox Foundation
- Jennerex, Transgene SA (Illkirch, France)
- Green Cross Corporation
- Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea
- Canadian Institute for Health Research (CIHR)
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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