title: Trial watch: Oncolytic viruses for cancer therapy.
abstract: Oncolytic virotherapy is emerging as a promising approach for the treatment of several neoplasms. The term "oncolytic viruses" is generally employed to indicate naturally occurring or genetically engineered attenuated viral particles that cause the demise of malignant cells while sparing their non-transformed counterparts. From a conceptual standpoint, oncolytic viruses differ from so-called "oncotropic viruses" in that only the former are able to kill cancer cells, even though both display a preferential tropism for malignant tissues. Of note, such a specificity can originate at several different steps of the viral cycle, including the entry of virions (transductional specificity) as well as their intracellular survival and replication (post-transcriptional and transcriptional specificity). During the past two decades, a large array of replication-competent and replication-incompetent oncolytic viruses has been developed and engineered to express gene products that would specifically promote the death of infected (cancer) cells. However, contrarily to long-standing beliefs, the antineoplastic activity of oncolytic viruses is not a mere consequence of the cytopathic effect, i.e., the lethal outcome of an intense, productive viral infection, but rather involves the elicitation of an antitumor immune response. In line with this notion, oncolytic viruses genetically modified to drive the local production of immunostimulatory cytokines exert more robust therapeutic effects than their non-engineered counterparts. Moreover, the efficacy of oncolytic virotherapy is significantly improved by some extent of initial immunosuppression (facilitating viral replication and spread) followed by the administration of immunostimulatory molecules (boosting antitumor immune responses). In this Trial Watch, we will discuss the results of recent clinical trials that have evaluated/are evaluating the safety and antineoplastic potential of oncolytic virotherapy.
authors.affiliation: Institut Gustave Roussy; Villejuif, France ; Université Paris-Sud/Paris XI; Le Kremlin-Bicêtre, France ; INSERM, U848; Villejuif, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Vacchelli
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Catherine
authors.initials: C
authors.lastname: Sautès-Fridman
authors.forename: Jérôme
authors.initials: J
authors.lastname: Galon
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Galluzzi
keywords: GM-CSF; HSV; JX594; immunotherapy; reolysin; talimogene laherparepvec
references.citation: Cancer Res. 2006 Jul 15;66(14):7185-94
references.pmid: 16849565
references.citation: Nat Med. 1997 Dec;3(12):1354-61
references.pmid: 9396605
references.citation: Mol Ther. 2013 Feb;21(2):348-57
references.pmid: 23011032
references.citation: Gene Ther. 2005 Jan;12(1):87-94
references.pmid: 15385953
references.citation: Int J Oncol. 2006 Oct;29(4):765-77
references.pmid: 16964374
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1223-1225
references.pmid: 23243584
references.citation: J Virol. 2009 Jun;83(11):5933-8
references.pmid: 19279088
references.citation: J Clin Oncol. 2002 May 1;20(9):2251-66
references.pmid: 11980996
references.citation: Methods Mol Biol. 2010;651:279-90
references.pmid: 20686972
references.citation: Gene Ther. 2003 Feb;10(4):292-303
references.pmid: 12595888
references.citation: Nat Biotechnol. 2012 Jul 10;30(7):658-70
references.pmid: 22781695
references.citation: Lancet. 2001 Feb 17;357(9255):525-6
references.pmid: 11229673
references.citation: Proc Natl Acad Sci U S A. 2001 May 22;98(11):6396-401
references.pmid: 11353831
references.citation: Gene Ther. 2006 Jul;13(14):1080-7
references.pmid: 16554839
references.citation: Cancer Gene Ther. 2000 May;7(5):732-8
references.pmid: 10830720
references.citation: Microbes Infect. 2005 Dec;7(15):1492-500
references.pmid: 16054416
references.citation: Mol Ther. 2004 Nov;10(5):958-66
references.pmid: 15509513
references.citation: Mol Ther. 2006 Jan;13(1):221-8
references.pmid: 16257582
references.citation: Science. 1991 May 10;252(5007):854-6
references.pmid: 1851332
references.citation: Mol Ther. 2010 Jul;18(7):1275-83
references.pmid: 20442708
references.citation: J Neurosurg. 2004 Jun;100(6):1049-59
references.pmid: 15200120
references.citation: Adv Virol. 2012;2012:805629
references.pmid: 22400027
references.citation: Cancer Res. 2012 Apr 1;72(7):1621-31
references.pmid: 22323527
references.citation: Gene Ther. 2006 Jul;13(13):1010-20
references.pmid: 16525479
references.citation: Clin Cancer Res. 2013 May 15;19(10):2734-44
references.pmid: 23493351
references.citation: Oncoimmunology. 2012 Mar 1;1(2):208-210
references.pmid: 22720244
references.citation: Gene Ther. 2000 May;7(10):867-74
references.pmid: 10845725
references.citation: Oncoimmunology. 2012 Jul 1;1(4):563-565
references.pmid: 22754788
references.citation: Int J Cancer. 2004 Aug 20;111(2):303-9
references.pmid: 15197787
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3933-41
references.pmid: 18559615
references.citation: Head Neck. 2008 Aug;30(8):1045-51
references.pmid: 18615711
references.citation: Nat Rev Cancer. 2002 Dec;2(12):938-50
references.pmid: 12459732
references.citation: Oncoimmunology. 2012 Jul 1;1(4):493-506
references.pmid: 22754768
references.citation: J Clin Oncol. 2001 Jan 15;19(2):289-98
references.pmid: 11208818
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8702-6
references.pmid: 8378352
references.citation: Adv Drug Deliv Rev. 2011 Mar 18;63(3):136-51
references.pmid: 20441782
references.citation: Clin Cancer Res. 2008 Nov 1;14(21):7127-37
references.pmid: 18981012
references.citation: Cancer. 1954 Jan;7(1):106-18
references.pmid: 13126905
references.citation: Ai Zheng. 2003 Dec;22(12):1307-10
references.pmid: 14693057
references.citation: Cancer Lett. 2007 Sep 8;254(2):178-216
references.pmid: 17383089
references.citation: J Virol. 2003 Aug;77(16):8843-56
references.pmid: 12885903
references.citation: Cancer. 1956 Nov-Dec;9(6):1211-8
references.pmid: 13383455
references.citation: Clin Cancer Res. 2006 Apr 15;12(8):2555-62
references.pmid: 16638865
references.citation: Hum Gene Ther. 1996 Jun 10;7(9):1095-101
references.pmid: 8773511
references.citation: Oncoimmunology. 2012 May 1;1(3):306-315
references.pmid: 22737606
references.citation: Nat Rev Microbiol. 2008 Jul;6(7):529-40
references.pmid: 18552863
references.citation: Eur J Immunol. 2000 May;30(5):1297-307
references.pmid: 10820375
references.citation: Cancer Res. 2002 Feb 15;62(4):1063-8
references.pmid: 11861383
references.citation: Nat Med. 2000 Aug;6(8):879-85
references.pmid: 10932224
references.citation: Oncoimmunology. 2012 Dec 1;1(9):1557-1576
references.pmid: 23264902
references.citation: J Lab Clin Med. 1956 Apr;47(4):573-82
references.pmid: 13307092
references.citation: Oncogene. 2011 Mar 10;30(10):1147-58
references.pmid: 21151176
references.citation: Future Virol. 2011 Sep;6(9):1045-1058
references.pmid: 21984883
references.citation: Gene Ther. 2008 Oct;15(20):1361-71
references.pmid: 18480846
references.citation: Invest New Drugs. 2013 Jun;31(3):696-706
references.pmid: 22886613
references.citation: J Virol. 1997 Jul;71(7):5560-9
references.pmid: 9188630
references.citation: Br J Cancer. 2006 Oct 23;95(8):1020-7
references.pmid: 17047650
references.citation: Hum Gene Ther. 2009 Sep;20(9):975-88
references.pmid: 19469693
references.citation: J Clin Oncol. 2009 Dec 1;27(34):5763-71
references.pmid: 19884534
references.citation: Cancer Gene Ther. 2011 Jun;18(6):435-43
references.pmid: 21394109
references.citation: Nat Med. 2013 Mar;19(3):329-36
references.pmid: 23396206
references.citation: J Virol. 2002 Aug;76(16):7932-41
references.pmid: 12133997
references.citation: Gene Ther. 1999 May;6(5):882-92
references.pmid: 10505114
references.citation: J Natl Cancer Inst. 2007 Nov 7;99(21):1623-33
references.pmid: 17971529
references.citation: Cancer Gene Ther. 2005 Aug;12(8):673-81
references.pmid: 15803147
references.citation: J Natl Cancer Inst. 2003 May 7;95(9):652-60
references.pmid: 12734316
references.citation: J Urol. 2012 Dec;188(6):2391-7
references.pmid: 23088985
references.citation: Cancer Res. 2003 Nov 1;63(21):7497-506
references.pmid: 14612551
references.citation: Cancer Gene Ther. 2006 Sep;13(9):845-55
references.pmid: 16710344
references.citation: Cancer Res. 2010 May 15;70(10):3890-5
references.pmid: 20424118
references.citation: Cell Death Differ. 2011 Sep;18(9):1403-13
references.pmid: 21072053
references.citation: Cancer Res. 2001 Oct 15;61(20):7464-72
references.pmid: 11606381
references.citation: Clin Cancer Res. 2004 Jul 1;10(13):4509-16
references.pmid: 15240543
references.citation: Clin Cancer Res. 2011 May 1;17(9):2807-18
references.pmid: 21346145
references.citation: Hum Gene Ther. 2005 Sep;16(9):1016-27
references.pmid: 16149900
references.citation: Annu Rev Immunol. 2002;20:825-52
references.pmid: 11861619
references.citation: Oncogene. 2003 Apr 10;22(14):2065-72
references.pmid: 12687009
references.citation: Ann Surg Oncol. 2010 Mar;17(3):718-30
references.pmid: 19915919
references.citation: Mol Ther. 2008 Feb;16(2):244-51
references.pmid: 18071336
references.citation: J Clin Oncol. 2003 Apr 15;21(8):1498-504
references.pmid: 12697873
references.citation: Gene Ther. 2004 Nov;11(22):1648-58
references.pmid: 15334111
references.citation: J Virol. 2010 Feb;84(3):1550-62
references.pmid: 19906911
references.citation: Mol Ther. 2011 Oct;19(10):1802-12
references.pmid: 21792179
references.citation: Blood. 1997 Mar 1;89(5):1642-53
references.pmid: 9057647
references.citation: Expert Opin Biol Ther. 2009 Jul;9(7):817-30
references.pmid: 19527106
references.citation: Mol Ther. 2004 May;9(5):650-7
references.pmid: 15120325
references.citation: Cancer Res. 2000 Aug 1;60(15):4251-5
references.pmid: 10945638
references.citation: Ann Surg. 2002 Jun;235(6):879-87
references.pmid: 12035046
references.citation: Cell Death Differ. 2012 Jan;19(1):107-20
references.pmid: 21760595
references.citation: J Nanobiotechnology. 2006 Feb 13;4:2
references.pmid: 16476163
references.citation: Cancer Treat Rev. 2011 Dec;37(8):618-32
references.pmid: 21232872
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1344-1354
references.pmid: 23243597
references.citation: Oncoimmunology. 2013 Jan 1;2(1):e22059
references.pmid: 23483796
references.citation: Cancer Gene Ther. 2006 Nov;13(11):1011-22
references.pmid: 16799468
references.citation: Hum Gene Ther. 2005 Sep;16(9):1014-5
references.pmid: 16149899
references.citation: Cancer. 2003 May 15;97(10):2576-87
references.pmid: 12733157
references.citation: Gene Ther. 2009 Jun;16(6):796-804
references.pmid: 19242529
references.citation: Annu Rev Immunol. 2013;31:51-72
references.pmid: 23157435
references.citation: Mol Ther. 2011 Oct;19(10):1913-22
references.pmid: 21772252
references.citation: Cancer Gene Ther. 2008 Dec;15(12):795-807
references.pmid: 18535620
references.citation: Cancer Cell. 2003 Oct;4(4):263-75
references.pmid: 14585354
references.citation: PLoS One. 2012;7(5):e36506
references.pmid: 22563505
references.citation: J Hepatol. 2013 Sep;59(3):583-94
references.pmid: 23567086
references.citation: Oncoimmunology. 2012 Sep 1;1(6):894-907
references.pmid: 23162757
references.citation: J Virol. 2006 Jul;80(13):6603-11
references.pmid: 16775347
references.citation: Oncoimmunology. 2012 May 1;1(3):326-333
references.pmid: 22737608
references.citation: Mol Cancer Res. 2006 Feb;4(2):61-70
references.pmid: 16513837
references.citation: Science. 1998 Nov 13;282(5392):1332-4
references.pmid: 9812900
references.citation: Cancer Gene Ther. 2012 Apr;19(4):238-46
references.pmid: 22158521
references.citation: J Virol. 1998 Nov;72(11):8893-903
references.pmid: 9765434
references.citation: Hum Gene Ther. 2012 May;23(5):484-91
references.pmid: 22171635
references.citation: Cancer Res. 2002 Sep 1;62(17):4968-76
references.pmid: 12208748
references.citation: Clin Cancer Res. 2006 Jan 1;12(1):305-13
references.pmid: 16397056
references.citation: Cancer Res. 2010 Jan 15;70(2):598-608
references.pmid: 20068158
references.citation: Oncoimmunology. 2012 Aug 1;1(5):699-716
references.pmid: 22934262
references.citation: Expert Opin Biol Ther. 2013 Apr;13(4):483-502
references.pmid: 23289598
references.citation: Lancet Oncol. 2008 Jun;9(6):533-42
references.pmid: 18495536
references.citation: Nat Methods. 2009 Aug;6(8):577-9
references.pmid: 19578384
references.citation: Curr Pharm Biotechnol. 2012 Jul;13(9):1842-51
references.pmid: 21740359
references.citation: Oncoimmunology. 2012 Oct 1;1(7):1167-1168
references.pmid: 23170267
references.citation: Mol Ther. 2007 Apr;15(4):651-9
references.pmid: 17299401
references.citation: Int J Cancer. 2012 Apr 15;130(8):1937-47
references.pmid: 21630267
references.citation: Cancer. 1974 Dec;34(6):1907-28
references.pmid: 4611607
references.citation: Blood. 2001 Jun 15;97(12):3746-54
references.pmid: 11389012
references.citation: Exp Gerontol. 2002 Jun;37(6):823-31
references.pmid: 12175482
references.citation: Mol Ther. 2009 Feb;17(2):389-94
references.pmid: 19018254
references.citation: Eur J Cancer. 2005 Oct;41(15):2280-7
references.pmid: 16143516
references.citation: Cancer. 2005 Aug 1;104(3):618-28
references.pmid: 15973737
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1271-1280
references.pmid: 23243590
references.citation: Mol Ther. 2010 May;18(5):929-35
references.pmid: 20179676
references.citation: Ann Surg Oncol. 2006 Aug;13(8):1078-84
references.pmid: 16865590
references.citation: Gene Ther. 2001 Mar;8(5):341-8
references.pmid: 11313809
references.citation: Nat Med. 2000 Jul;6(7):821-5
references.pmid: 10888934
references.citation: Oncoimmunology. 2013 Feb 1;2(2):e22691
references.pmid: 23524510
references.citation: Curr Opin Mol Ther. 2008 Feb;10(1):38-45
references.pmid: 18228180
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2208-13
references.pmid: 10681459
references.citation: Nat Rev Drug Discov. 2012 Feb 03;11(3):215-33
references.pmid: 22301798
references.citation: PLoS Pathog. 2008 May 30;4(5):e1000018
references.pmid: 18516228
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1323-1343
references.pmid: 23243596
references.citation: BMC Cancer. 2012 Mar 21;12:99
references.pmid: 22436661
references.citation: Cancer Gene Ther. 2011 Mar;18(3):167-75
references.pmid: 21102422
references.citation: Gene Ther. 2000 Nov;7(21):1824-32
references.pmid: 11110414
references.citation: J Virol. 2000 May;74(10):4765-75
references.pmid: 10775615
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):2909-14
references.pmid: 21282607
references.citation: Oncoimmunology. 2013 Feb 1;2(2):e23082
references.pmid: 23525565
references.citation: Nat Med. 2008 Oct;14(10):1123-7
references.pmid: 18836461
references.citation: N Engl J Med. 2003 Jan 16;348(3):255-6
references.pmid: 12529469
references.citation: Clin Cancer Res. 2003 Feb;9(2):555-61
references.pmid: 12576418
references.citation: Oncoimmunology. 2012 Sep 1;1(6):979-981
references.pmid: 23162778
references.citation: Oncoimmunology. 2012 Sep 1;1(6):874-883
references.pmid: 23162755
references.citation: Hum Gene Ther. 2010 Sep;21(9):1119-28
references.pmid: 20486770
references.citation: Oncoimmunology. 2012 Oct 1;1(7):1111-1134
references.pmid: 23170259
references.citation: Oncoimmunology. 2012 Jan 1;1(1):28-37
references.pmid: 22720209
references.citation: Cancer Gene Ther. 2007 Nov;14(11):885-93
references.pmid: 17704755
references.citation: Cytokine Growth Factor Rev. 2010 Apr-Jun;21(2-3):177-83
references.pmid: 20219409
references.citation: Cancer Res. 2012 May 1;72(9):2327-38
references.pmid: 22396493
references.citation: AMA Arch Derm Syphilol. 1950 Nov;62(5):694-5
references.pmid: 14770525
references.citation: Cancer Gene Ther. 1999 Sep-Oct;6(5):409-22
references.pmid: 10505851
references.citation: Int J Pharm. 2008 Apr 16;354(1-2):3-8
references.pmid: 17904316
references.citation: Gene Ther. 2005 Jan;12(2):147-59
references.pmid: 15372069
references.citation: Cancer Gene Ther. 2003 Aug;10(8):589-90
references.pmid: 12872140
references.citation: Nat Med. 2008 Nov;14(11):1278-83
references.pmid: 18953352
references.citation: Mol Ther. 2008 Aug;16(8):1437-43
references.pmid: 18560417
references.citation: J Nucl Med. 2006 Jul;47(7):1136-43
references.pmid: 16818948
references.citation: Oncoimmunology. 2012 Dec 1;1(9):1661-1663
references.pmid: 23264929
references.citation: Nat Rev Clin Oncol. 2010 Nov;7(11):653-64
references.pmid: 20838415
references.citation: J Virol. 2011 Jun;85(11):5679-84
references.pmid: 21450833
references.citation: Mol Ther. 2009 Jan;17(1):199-207
references.pmid: 18957964
references.citation: Mol Ther. 2010 Feb;18(2):429-34
references.pmid: 19935775
references.citation: Clin Cancer Res. 2010 Nov 1;16(21):5277-87
references.pmid: 20978148
references.citation: J Clin Oncol. 2002 Mar 15;20(6):1562-9
references.pmid: 11896105
references.citation: Oncoimmunology. 2013 Jan 1;2(1):e22789
references.pmid: 23482847
references.citation: Clin Cancer Res. 2006 Nov 15;12(22):6737-47
references.pmid: 17121894
references.citation: J Virol. 2006 Jun;80(11):5145-55
references.pmid: 16698995
references.citation: Cancer Res. 2002 Nov 1;62(21):6070-9
references.pmid: 12414631
references.citation: Trans N Y Acad Sci. 1960 Jun;22:657-73
references.pmid: 13833074
references.citation: Oncoimmunology. 2012 Nov 1;1(8):1417-1419
references.pmid: 23243613
references.citation: Clin Cancer Res. 2000 Mar;6(3):798-806
references.pmid: 10741699
references.citation: Arch Virol. 2003 Apr;148(4):813-25
references.pmid: 12664303
references.citation: Nat Rev Mol Cell Biol. 2011 Jun;12(6):385-92
references.pmid: 21527953
references.citation: Nat Rev Cancer. 2006 Sep;6(9):688-701
references.pmid: 16900224
references.citation: J Natl Cancer Inst. 2001 Jul 4;93(13):998-1007
references.pmid: 11438565
references.citation: N Engl J Med. 1964 Sep 24;271:645-51
references.pmid: 14170843
references.citation: Acta Otolaryngol. 2006 Oct;126(10):1115-7
references.pmid: 16923721
references.citation: Invest New Drugs. 2012 Apr;30(2):568-81
references.pmid: 21170760
references.citation: Science. 2003 Oct 17;302(5644):415-9
references.pmid: 14564000
references.citation: Mol Ther. 2012 Oct;20(10):1998-2003
references.pmid: 22871663
references.citation: Cancer Biol Ther. 2006 Apr;5(4):435-40
references.pmid: 16575205
references.citation: Clin Cancer Res. 2012 Apr 1;18(7):2080-9
references.pmid: 22316603
references.citation: Gene Ther. 2002 Mar;9(6):398-406
references.pmid: 11960316
references.citation: Mol Genet Genomics. 2009 Oct;282(4):417-35
references.pmid: 19701652
references.citation: Lancet. 2001 Feb 24;357(9256):614
references.pmid: 11558496
references.citation: Int Rev Immunol. 1991;7(4):259-87
references.pmid: 1663989
references.citation: Cancer Res. 1999 Jan 15;59(2):410-3
references.pmid: 9927055
references.citation: Mol Ther. 2003 Nov;8(5):746-55
references.pmid: 14599807
references.citation: Clin Cancer Res. 2010 Aug 1;16(15):4005-15
references.pmid: 20670951
references.citation: Cancer Gene Ther. 2005 Oct;12(10):835-48
references.pmid: 15891772
references.citation: Oncoimmunology. 2013 Apr 1;2(4):e23803
references.pmid: 23734328
references.citation: Cancer Res. 2003 Oct 15;63(20):6877-84
references.pmid: 14583486
references.citation: Cancer Gene Ther. 2001 Dec;8(12):958-65
references.pmid: 11781658
references.citation: Mol Ther. 2011 Aug;19(8):1558-68
references.pmid: 21468000
references.citation: Gene Ther. 2005 Mar;12(5):437-45
references.pmid: 15647767
references.citation: Oncogene. 2001 Nov 26;20(54):7855-65
references.pmid: 11753668
references.citation: Ai Zheng. 2004 Dec;23(12):1666-70
references.pmid: 15601557
references.citation: Clin Cancer Res. 2009 Feb 15;15(4):1317-25
references.pmid: 19228733
references.citation: J Virol Methods. 2009 Jan;155(1):44-54
references.pmid: 18951922
references.citation: Oncoimmunology. 2012 Mar 1;1(2):179-188
references.pmid: 22720239
references.citation: Cancer Res. 2002 Aug 15;62(16):4656-62
references.pmid: 12183422
references.citation: Curr Pharm Biotechnol. 2012 Jul;13(9):1834-41
references.pmid: 21740364