title: Viro-immune therapy: A new strategy for treatment of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses (TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1 (PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
authors.affiliation: Andrea Marie Ibrahim, Yao-He Wang, Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1M6BQ London, United Kingdom.
authors.forename: Andrea Marie
authors.initials: AM
authors.lastname: Ibrahim
authors.affiliation: Andrea Marie Ibrahim, Yao-He Wang, Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, EC1M6BQ London, United Kingdom.
authors.forename: Yao-He
authors.initials: YH
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000276:immunology / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D054884:Host-Pathogen Interactions; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D058990:Molecular Targeted Therapy; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology / Q000472:pathogenicity*; D010190:Pancreatic Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology*; D016896:Treatment Outcome; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines
keywords: Anti-cytotoxic T-lymphocyte-associate protein 4; Anti-programmed death receptor 1; Anti-programmed death receptor ligand 1; Cancer vaccine; Immune checkpoint blockade inhibitors; Immunotherapy; Oncolytic viruses; Pancreatic cancer; Pancreatic ductal adenocarcinoma
references.citation: J Am Coll Surg. 1999 Jul;189(1):1-7
references.pmid: 10401733
references.citation: J Exp Med. 2000 Oct 2;192(7):1027-34
references.pmid: 11015443
references.citation: Nat Med. 2000 Oct;6(10):1134-9
references.pmid: 11017145
references.citation: J Clin Oncol. 2001 Jan 1;19(1):145-56
references.pmid: 11134207
references.citation: Nat Immunol. 2001 Mar;2(3):261-8
references.pmid: 11224527
references.citation: Int J Cancer. 2001 May 1;92(3):441-50
references.pmid: 11291084
references.citation: Clin Cancer Res. 2001 Sep;7(9):2887-97
references.pmid: 11555607
references.citation: Nat Med. 2002 Aug;8(8):793-800
references.pmid: 12091876
references.citation: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12293-7
references.pmid: 12218188
references.citation: Cancer Gene Ther. 2002 Dec;9(12):1036-42
references.pmid: 12522442
references.citation: Clin Cancer Res. 2003 Feb;9(2):555-61
references.pmid: 12576418
references.citation: Clin Cancer Res. 2003 Mar;9(3):1218-23
references.pmid: 12631628
references.citation: Cell. 1992 Dec 24;71(7):1065-8
references.pmid: 1335362
references.citation: J Virol. 2004 Jan;78(2):912-21
references.pmid: 14694122
references.citation: Pancreas. 2004 Jan;28(1):e26-31
references.pmid: 14707745
references.citation: N Engl J Med. 2004 Mar 18;350(12):1200-10
references.pmid: 15028824
references.citation: J Exp Med. 2004 Aug 2;200(3):297-306
references.pmid: 15289501
references.citation: Cancer Res. 2004 Sep 1;64(17):6337-43
references.pmid: 15342423
references.citation: Cancer Immunol Immunother. 2005 Mar;54(3):254-64
references.pmid: 15372205
references.citation: Cancer Cell. 2004 Dec;6(6):611-23
references.pmid: 15607965
references.citation: J Clin Oncol. 2005 Feb 1;23(4):720-31
references.pmid: 15613691
references.citation: Hum Gene Ther. 2005 Aug;16(8):996-1005
references.pmid: 16076257
references.citation: Int J Oncol. 2005 Oct;27(4):901-6
references.pmid: 16142304
references.citation: Cancer Res. 2005 Nov 15;65(22):10555-61
references.pmid: 16288048
references.citation: Oncology (Williston Park). 2005 Nov;19(12):1557-65; discussion 1566, 1568 passim
references.pmid: 16396151
references.citation: Expert Rev Vaccines. 2006 Feb;5(1):9-19
references.pmid: 16451103
references.citation: Genes Dev. 2006 May 15;20(10):1218-49
references.pmid: 16702400
references.citation: Adv Drug Deliv Rev. 2006 Oct 1;58(8):931-47
references.pmid: 17030074
references.citation: Ann Oncol. 2007 Feb;18(2):226-32
references.pmid: 17116643
references.citation: Clin Cancer Res. 2006 Nov 15;12(22):6737-47
references.pmid: 17121894
references.citation: J Exp Med. 1991 Sep 1;174(3):561-9
references.pmid: 1714933
references.citation: Nat Med. 2007 Jan;13(1):84-8
references.pmid: 17159987
references.citation: J Cell Biochem. 2007 Jul 1;101(4):887-907
references.pmid: 17266048
references.citation: Mol Ther. 2007 Apr;15(4):651-9
references.pmid: 17299401
references.citation: Curr Cancer Drug Targets. 2007 Mar;7(2):141-8
references.pmid: 17346105
references.citation: Am J Gastroenterol. 2007 Jul;102(7):1377-82
references.pmid: 17403071
references.citation: Clin Cancer Res. 2007 Apr 1;13(7):2151-7
references.pmid: 17404099
references.citation: Mol Cancer Ther. 2007 Apr;6(4):1186-97
references.pmid: 17406031
references.citation: J Clin Oncol. 2007 May 20;25(15):1960-6
references.pmid: 17452677
references.citation: J Hepatobiliary Pancreat Surg. 2007;14(3):224-32
references.pmid: 17520196
references.citation: J Clin Oncol. 2007 Jun 20;25(18):2546-53
references.pmid: 17577033
references.citation: Int J Pharm. 2008 Apr 16;354(1-2):3-8
references.pmid: 17904316
references.citation: J Clin Invest. 2007 Nov;117(11):3350-8
references.pmid: 17965776
references.citation: J Transl Med. 2007 Nov 26;5:60
references.pmid: 18039393
references.citation: J Clin Oncol. 2008 Jan 10;26(2):313-25
references.pmid: 18086794
references.citation: Annu Rev Immunol. 2008;26:677-704
references.pmid: 18173375
references.citation: Cancer Res. 2008 Feb 1;68(3):918-26
references.pmid: 18245495
references.citation: Am Fam Physician. 2008 Feb 1;77(3):311-9
references.pmid: 18297955
references.citation: Clin Cancer Res. 2008 Mar 1;14(5):1455-63
references.pmid: 18316569
references.citation: JAMA. 2008 Mar 5;299(9):1019-26
references.pmid: 18319412
references.citation: J Cancer Res Clin Oncol. 2008 Sep;134(9):1021-7
references.pmid: 18347814
references.citation: BMC Cancer. 2008 Mar 28;8:82
references.pmid: 18373843
references.citation: Mol Ther. 2008 Jul;16(7):1217-26
references.pmid: 18431359
references.citation: Immunity. 2008 May;28(5):710-22
references.pmid: 18468462
references.citation: Cancer Lett. 2008 Sep 8;268(1):98-109
references.pmid: 18486325
references.citation: Nat Rev Immunol. 2008 Jun;8(6):467-77
references.pmid: 18500231
references.citation: Science. 1991 May 10;252(5007):854-6
references.pmid: 1851332
references.citation: Curr Gene Ther. 2008 Jun;8(3):208-21
references.pmid: 18537595
references.citation: Gene Ther. 2008 Dec;15(24):1579-92
references.pmid: 18701918
references.citation: Hum Gene Ther. 2008 Dec;19(12):1383-400
references.pmid: 18771358
references.citation: Science. 2008 Sep 26;321(5897):1801-6
references.pmid: 18772397
references.citation: Nat Rev Cancer. 2009 Jan;9(1):64-71
references.pmid: 19104515
references.citation: Gene Ther. 2009 May;16(5):669-80
references.pmid: 19225547
references.citation: Arch Pathol Lab Med. 2009 Mar;133(3):365-74
references.pmid: 19260742
references.citation: Arch Pathol Lab Med. 2009 Mar;133(3):375-81
references.pmid: 19260743
references.citation: Neoplasia. 2009 May;11(5):497-508
references.pmid: 19412434
references.citation: Blood. 2009 Aug 20;114(8):1537-44
references.pmid: 19423728
references.citation: Expert Opin Biol Ther. 2009 Sep;9(9):1163-76
references.pmid: 19637971
references.citation: PLoS One. 2009 Aug 04;4(8):e6514
references.pmid: 19652721
references.citation: Clin Cancer Res. 2009 Oct 1;15(19):6158-66
references.pmid: 19773377
references.citation: Cancer Gene Ther. 2010 Apr;17(4):244-55
references.pmid: 19798121
references.citation: Curr Gene Ther. 2009 Oct;9(5):341-55
references.pmid: 19860649
references.citation: Gene Ther. 2010 Feb;17(2):281-7
references.pmid: 19890355
references.citation: Nat Rev Microbiol. 2010 Jan;8(1):62-73
references.pmid: 19966816
references.citation: Hum Vaccin. 2010 Jan;6(1):78-83
references.pmid: 20061802
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):541-53
references.pmid: 20068104
references.citation: Nat Rev Clin Oncol. 2010 Mar;7(3):163-72
references.pmid: 20101258
references.citation: World J Surg. 2010 May;34(5):1059-65
references.pmid: 20145927
references.citation: Cancer Gene Ther. 2010 Jul;17(7):476-83
references.pmid: 20168350
references.citation: PLoS Med. 2010 Apr 20;7(4):e1000267
references.pmid: 20422030
references.citation: N Engl J Med. 2010 Apr 29;362(17):1605-17
references.pmid: 20427809
references.citation: Int J Cancer. 2011 Feb 15;128(4):908-19
references.pmid: 20473905
references.citation: J Clin Oncol. 2010 Jul 1;28(19):3167-75
references.pmid: 20516446
references.citation: N Engl J Med. 2010 Aug 19;363(8):711-23
references.pmid: 20525992
references.citation: Viruses. 2010 Jan;2(1):78-106
references.pmid: 20543907
references.citation: Br J Surg. 2010 Sep;97(9):1385-94
references.pmid: 20629009
references.citation: Clin Cancer Res. 2010 Aug 1;16(15):4005-15
references.pmid: 20670951
references.citation: J Immunother. 2010 Oct;33(8):828-33
references.pmid: 20842054
references.citation: Cancer Gene Ther. 2011 Mar;18(3):167-75
references.pmid: 21102422
references.citation: Mol Ther. 2011 Feb;19(2):335-44
references.pmid: 21119618
references.citation: Cancer Microenviron. 2010 Mar 19;3(1):83-95
references.pmid: 21209776
references.citation: Ann Surg. 2011 Feb;253(2):328-35
references.pmid: 21217520
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Science. 2011 Mar 25;331(6024):1565-70
references.pmid: 21436444
references.citation: Science. 2011 Mar 25;331(6024):1612-6
references.pmid: 21436454
references.citation: Mol Ther. 2011 Jun;19(6):1008-16
references.pmid: 21505424
references.citation: Cancer Immunol Immunother. 2011 Aug;60(8):1097-107
references.pmid: 21547597
references.citation: N Engl J Med. 2011 May 12;364(19):1817-25
references.pmid: 21561347
references.citation: Rev Med Virol. 2011 Jul;21(4):213-26
references.pmid: 21626603
references.citation: Expert Rev Mol Med. 2011 May 18;13:e18
references.pmid: 21676289
references.citation: Cancer Gene Ther. 2011 Aug;18(8):598-608
references.pmid: 21701532
references.citation: Br J Surg. 2011 Oct;98(10):1455-62
references.pmid: 21717423
references.citation: Pancreas. 2012 Mar;41(2):195-205
references.pmid: 21792083
references.citation: Gene Ther. 2011 Dec;18(12):1157-65
references.pmid: 21975464
references.citation: Nat Rev Cancer. 2011 Oct 24;11(11):805-12
references.pmid: 22020206
references.citation: Gene Ther. 2012 Oct;19(10):988-98
references.pmid: 22071969
references.citation: J Transl Med. 2011 Nov 28;9:204
references.pmid: 22123319
references.citation: Cancer Immunol Immunother. 2012 Jul;61(7):1019-31
references.pmid: 22146893
references.citation: Nature. 2011 Dec 21;480(7378):480-9
references.pmid: 22193102
references.citation: Gastroenterology. 2012 Apr;142(4):730-733.e9
references.pmid: 22226782
references.citation: Mol Ther. 2012 Apr;20(4):759-68
references.pmid: 22233582
references.citation: Cancer Lett. 2012 Jun 28;319(2):154-163
references.pmid: 22261331
references.citation: Nat Rev Cancer. 2012 Mar 22;12(4):252-64
references.pmid: 22437870
references.citation: Sci Transl Med. 2012 Mar 28;4(127):127ra37
references.pmid: 22461641
references.citation: Cancer Immunol Immunother. 2012 Nov;61(11):2113-23
references.pmid: 22576056
references.citation: N Engl J Med. 2012 Jun 28;366(26):2443-54
references.pmid: 22658127
references.citation: Cancer Cell. 2012 Jun 12;21(6):836-47
references.pmid: 22698407
references.citation: Nat Biotechnol. 2012 Jul 10;30(7):658-70
references.pmid: 22781695
references.citation: Surgery. 2012 Sep;152(3):441-8
references.pmid: 22853858
references.citation: Clin Cancer Res. 2012 Aug 15;18(16):4266-76
references.pmid: 22896693
references.citation: Ann Oncol. 2012 Sep;23 Suppl 8:viii6-9
references.pmid: 22918931
references.citation: Gut. 2013 Mar;62(3):339-47
references.pmid: 23135763
references.citation: J Gastrointest Surg. 2013 Jan;17(1):94-100; discussion p. 100-1
references.pmid: 23229886
references.citation: Mol Biol Rep. 2013 Sep;40(9):5397-405
references.pmid: 23666064
references.citation: N Engl J Med. 2013 Jul 11;369(2):134-44
references.pmid: 23724846
references.citation: N Engl J Med. 2013 Jul 11;369(2):122-33
references.pmid: 23724867
references.citation: Ann Surg. 2013 Dec;258(6):1040-50
references.pmid: 23799421
references.citation: Gastroenterology. 2013 Nov;145(5):1121-32
references.pmid: 23891972
references.citation: J Immunother. 2013 Sep;36(7):382-9
references.pmid: 23924790
references.citation: Ann Surg Oncol. 2013 Dec;20 Suppl 3:S725-30
references.pmid: 24046118
references.citation: JAMA. 2013 Oct 9;310(14):1473-81
references.pmid: 24104372
references.citation: N Engl J Med. 2013 Oct 31;369(18):1691-703
references.pmid: 24131140
references.citation: Cancer Res. 2013 Dec 15;73(24):7189-7198
references.pmid: 24177180
references.citation: Nat Med. 2013 Nov;19(11):1389-400
references.pmid: 24202392
references.citation: Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20212-7
references.pmid: 24277834
references.citation: Proc Natl Acad Sci U S A. 1987 Mar;84(5):1369-73
references.pmid: 2434954
references.citation: Cancer Gene Ther. 2014 Jan;21(1):12-23
references.pmid: 24384772
references.citation: Nat Rev Clin Oncol. 2014 Feb;11(2):91-9
references.pmid: 24445516
references.citation: Sci Transl Med. 2014 Mar 5;6(226):226ra32
references.pmid: 24598590
references.citation: New J Sci. 2014 Jan 5;2014:null
references.pmid: 24634791
references.citation: Cancer Immunol Res. 2014 Apr;2(4):295-300
references.pmid: 24764576
references.citation: Cancer Immunol Res. 2014 Mar;2(3):187-93
references.pmid: 24778314
references.citation: Ann Oncol. 2014 Sep;25(9):1750-5
references.pmid: 24907635
references.citation: Cancer Immunol Res. 2014 Jul;2(7):616-31
references.pmid: 24942756
references.citation: Lancet Oncol. 2014 Jul;15(8):829-40
references.pmid: 24954781
references.citation: Clin Cancer Res. 2014 Oct 1;20(19):4982-4
references.pmid: 24970841
references.citation: Nat Rev Cancer. 2014 Aug;14(8):559-67
references.pmid: 24990523
references.citation: Mol Ther. 2014 Nov;22(11):1949-59
references.pmid: 25156126
references.citation: World J Gastroenterol. 2014 Aug 28;20(32):11142-59
references.pmid: 25170201
references.citation: Onco Targets Ther. 2014 Aug 19;7:1465-72
references.pmid: 25170273
references.citation: J Immunother. 2015 Jan;38(1):1-11
references.pmid: 25415283
references.citation: Clin Cancer Res. 2015 Jan 15;21(2):405-16
references.pmid: 25416195
references.citation: N Engl J Med. 2014 Nov 27;371(22):2140-1
references.pmid: 25427123
references.citation: Nature. 2014 Nov 27;515(7528):577-81
references.pmid: 25428507
references.citation: Pharmacol Ther. 2015 Jun;150:23-32
references.pmid: 25583297
references.citation: J Clin Oncol. 2015 Apr 20;33(12):1325-33
references.pmid: 25584002
references.citation: Nat Med. 2015 May;21(5):530-6
references.pmid: 25894825
references.citation: Cancer Res. 2015 Jul 1;75(13):2629-40
references.pmid: 25952647
references.citation: Cancer Immunol Res. 2015 May 12;3(6):590-597
references.pmid: 25968457
references.citation: Nat Rev Drug Discov. 2015 Jun;14(6):369-71
references.pmid: 26027526
references.citation: World J Gastroenterol. 2015 May 28;21(20):6127-45
references.pmid: 26034349
references.citation: J Surg Oncol. 2015 Jun;111(8):1028-34
references.pmid: 26073887
references.citation: Oncolytic Virother. 2014 Feb 17;3:35-46
references.pmid: 27512661
references.citation: Arch Surg. 1985 Aug;120(8):899-903
references.pmid: 4015380
references.citation: Immunity. 1995 Nov;3(5):541-7
references.pmid: 7584144
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
references.pmid: 8097319
references.citation: Science. 1996 Mar 22;271(5256):1734-6
references.pmid: 8596936
references.citation: Annu Rev Immunol. 1996;14:233-58
references.pmid: 8717514
references.citation: Vaccine. 1997 Apr-May;15(6-7):759-68
references.pmid: 9178479
references.citation: Cancer Res. 1997 Jun 1;57(11):2140-3
references.pmid: 9187111
references.citation: J Clin Oncol. 1997 Jun;15(6):2403-13
references.pmid: 9196156
references.citation: Cancer Res. 1997 Aug 1;57(15):3126-30
references.pmid: 9242437
references.citation: EMBO J. 1998 Jun 15;17(12):3351-62
references.pmid: 9628872