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

被引：683

作者：

Heo, Jeong ^{[1
,2
]}

Reid, Tony ^{[3
]}

Ruo, Leyo ^{[4
]}

Breitbach, Caroline J. ^{[5
]}

Rose, Steven ^{[3
]}

Bloomston, Mark ^{[6
]}

Cho, Mong ^{[1
,2
]}

Lim, Ho Yeong ^{[7
]}

Chung, Hyun Cheol ^{[8
]}

Kim, Chang Won ^{[1
,2
]}

Burke, James ^{[5
]}

Lencioni, Riccardo ^{[9
]}

Hickman, Theresa ^{[5
]}

Moon, Anne ^{[5
]}

Lee, Yeon Sook ^{[10
]}

Kim, Mi Kyeong ^{[10
]}

Daneshmand, Manijeh ^{[11
]}

Dubois, Kara ^{[5
]}

Longpre, Lara ^{[5
]}

Ngo, Minhtran ^{[12
,13
]}

Rooney, Cliona ^{[12
,13
,14
]}

Bell, John C. ^{[5
,11
]}

Rhee, Byung-Geon ^{[15
]}

Patt, Richard ^{[16
]}

Hwang, Tae-Ho ^{[10
,17
]}

Kirn, David H. ^{[5
]}

机构：

[1] Pusan Natl Univ, Dept Internal Med, Pusan, South Korea

[2] Pusan Natl Univ Hosp, Med Res Inst, Pusan, South Korea

[3] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[4] McMaster Univ, Dept Surg, Med Ctr, Hamilton, ON L8S 4L8, Canada

[5] Jennerex Inc, San Francisco, CA USA

[6] Ohio State Univ, Dept Surg, Ctr Comprehens Canc, Columbus, OH 43210 USA

[7] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Med,Div Hematol Oncol, Seoul, South Korea

[8] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Yongdong Severance Hosp, Seoul, South Korea

[9] Univ Pisa, Sch Med, Div Diagnost Imaging & Intervent, I-56100 Pisa, Italy

[10] SillaJen Inc, Pusan, South Korea

[11] Ottawa Hosp Res Inst, Ctr Innovat Canc Therapeut, Ottawa, ON, Canada

[12] Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA

[13] Baylor Coll Med, Houston, TX 77030 USA

[14] Texas Childrens Hosp, Houston, TX 77030 USA

[15] Green Cross Co, Yongin, South Korea

[16] RadMD, Doylestown, PA USA

[17] Pusan Natl Univ, Dept Pharmacol, Pusan, South Korea

来源：

NATURE MEDICINE | 2013年 / 19卷 / 03期

关键词：

ADVANCED HEPATOCELLULAR-CARCINOMA; MODIFIED RECIST; POXVIRUS; SORAFENIB; VIROTHERAPY; DELIVERY; CRITERIA; THERAPY;

D O I：

10.1038/nm.3089

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：329 / 336

页数：8

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