Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans

被引：429

作者：

Breitbach, Caroline J. ^{[1
]}

Burke, James ^{[2
]}

Jonker, Derek ^{[3
,4
]}

Stephenson, Joe ^{[5
]}

Haas, Andrew R. ^{[6
]}

Chow, Laura Q. M. ^{[3
,4
]}

Nieva, Jorge ^{[2
]}

Hwang, Tae-Ho ^{[7
]}

Moon, Anne ^{[1
]}

Patt, Richard ^{[8
]}

Pelusio, Adina ^{[1
]}

Le Boeuf, Fabrice ^{[3
]}

Burns, Joe ^{[3
,4
]}

Evgin, Laura ^{[3
,4
]}

De Silva, Naomi ^{[3
,4
]}

Cvancic, Sara ^{[3
,4
]}

Robertson, Terri ^{[1
]}

Je, Ji-Eun ^{[7
]}

Lee, Yeon-Sook ^{[7
]}

Parato, Kelley ^{[3
]}

Diallo, Jean-Simon ^{[3
]}

Fenster, Aaron ^{[9
]}

Daneshmand, Manijeh ^{[3
,4
]}

Bell, John C. ^{[3
,4
]}

Kirn, David H. ^{[1
]}

机构：

[1] Jennerex Inc, San Francisco, CA 94111 USA

[2] Billings Clin, Dept Hematol Oncol, Billings, MT 59101 USA

[3] Ottawa Hosp Res Inst, Ottawa, ON K1H 8L6, Canada

[4] Univ Ottawa, Ottawa, ON K1N 6N5, Canada

[5] Canc Ctr Carolinas, Greenville, SC 29605 USA

[6] Univ Penn, Med Ctr, Philadelphia, PA 19104 USA

[7] Pusan Natl Univ, Pusan 609735, South Korea

[8] RadMD, Doylestown, PA 18901 USA

[9] Robarts Res Inst, London, ON N6A 5K8, Canada

来源：

NATURE | 2011年 / 477卷 / 7362期

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

VACCINIA VIRUS; GM-CSF; IMATINIB MESYLATE; THYMIDINE KINASE; MEASLES-VIRUS; GROWTH-FACTOR; THERAPY; TUMORS; CRITERIA; PROGRESS;

D O I：

10.1038/nature10358

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity(1). Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

引用

页码：99 / U102

页数：6

共 30 条

[1] DECREASED VIRULENCE OF RECOMBINANT VACCINIA VIRUS EXPRESSION VECTORS IS ASSOCIATED WITH A THYMIDINE KINASE-NEGATIVE PHENOTYPE [J].