250:
662:, however, proved reasonably effective in a proportion of cases. During these trials a plethora of reports emerged challenging the underlying p53-selectivity, with some reports showing that in some cancers with a wild-type p53 ONYX-015 actually did better than in their mutant p53 counterparts. These reports slowed the advancement through Phase III trials in the US, however recently China licensed
524:
transgenes, which can be introduced into the ColoAd1 genome without compromising the selectivity or activity of the virus. Recent studies with ColoAd1 have shown a unique mechanism of cell death similar to
Oncosis with expression of inflammatory cell death markers and cell membrane blistering and have highlighted mechanisms by which ColoAd1 alters host cell metabolism to facilitate replication.
262:(miRNA) artificial target sites or miRNA response elements (MREs). Differential expression of miRNAs between healthy tissues and tumors permit to engineer oncolytic viruses in order to have their ability to replicate impaired in those tissues of interest while allowing its replication in the tumor cells.
625:
from PsiOxus
Therapeutics has entered Phase I/II clinical study with its oncolytic vaccine. Phase I of the trial recruited patients with metastatic solid tumors and showed evidence for virus replication within tumour sites after intravenous delivery. The second phase of the ColoAd1 study will involve
518:
step provides a large random pool of viral candidates which can then be passed through a series of selection steps designed to lead towards a pre-specified outcome (e.g. higher tumor specific activity) without requiring any previous knowledge of the resultant viral mechanisms that are responsible for
1625:
Cerullo V, Pesonen S, Diaconu I, Escutenaire S, Arstila PT, Ugolini M, Nokisalmi P, Raki M, Laasonen L, Särkioja M, Rajecki M, Kangasniemi L, Guse K, Helminen A, Ahtiainen L, Ristimäki A, Räisänen-Sokolowski A, Haavisto E, Oksanen M, Karli E, Karioja-Kallio A, Holm SL, Kouri M, Joensuu T, Kanerva A,
432:
lab work, these viruses do not specifically infect cancer cells, but they still kill cancer cells preferentially. While overall survival rates are not known, short-term response rates are approximately doubled for H101 plus chemotherapy when compared to chemotherapy alone. It appears to work best
2009:
John
Nemunaitis, Ian Ganly, Fadlo Khuri, James Arseneau, Joseph Kuhn, Todd McCarty, Stephen Landers, Phillip Maples, Larry Rome, Britta Randlev, Tony Reid, Sam Kaye, David Kirn (2000). "Selective Replication and Oncolysis in p53 Mutant Tumors with ONYX-015, an E1B-55kD Gene-deleted Adenovirus, in
393:
Oncolytic adenoviruses have been genetically modified with transgene encoding for granulocyte-macrophage colony-stimulating factor (GM-CSF) to enhance tumor antigens presentation by antigen-presenting cells (APCs). This approach aims to improve recognition of tumor by T-cell and subsequent immune
185:
end of the coat protein successfully altered viral tropism. The addition of larger peptides to the C-terminus is not viable because it reduces adenovirus integrity, possibly due to an effect on fiber trimerisation. The fiber protein also contains an HI-loop structure, which can tolerate peptide
2764:
Khuri F, Nemunaitis J, Ganly I, Arseneau J, Tannock I, Romel L, Gore M, Ironside J, MacDougall R, Heise C, Randlev B, Gillenwater AM, Bruso P, Kaye SB, Hong WK, Kirn DH (2000). "A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and
523:
and a broad spectrum of anti-cancer activity in common solid tumours. The therapeutic efficacy of ColoAd1 is currently being evaluated in three ongoing clinical trials (see the EU Clinical Trials
Register for further details). ColoAd1 potency can be further enhanced via the use of therapeutic
382:
Immunostimulatory genes Like interferon α (IFNα), tumor necrosis factor alpha (TNFα), and interleukin 12 (IL-12) have been integrated into oncolytic adenovirus to enhance immune response inside the tumor microenvironment. When these molecules selectively expressed in tumor cells, oncolytic
493:
vaccines for the potential use as cancer treatment. However, recent data suggests that it may not be the best virus serotype for deriving all oncolytic agents for treating human malignancies. For example, oncolytic vaccines based on the Ad5 serotype have relatively poor clinical efficacy as
510:. It was created using a process of “directed evolution”. This involves the creation of new viral variants or serotypes specifically directed against tumour cells via rounds of directed selection using large populations of randomly generated recombinant precursor viruses. The increased
2750:
404:
Oncolytic adenoviruses have been genetically engineered to express checkpoint inhibitors (CTLA-4, anti-PD-L1 antibodies) to release brake of T-cell activity , and to express costimulatory molecules (CD40L, 4-1BBL) to augment T-cell activation and proliferation,
238:(PSA), whose expression is greatly elevated in prostate cancer. CN706 is a CRAd with a PSA tumour-specific promoter driving expression of the adenoviral E1A gene, required for viral replication. The CN706 titre is significantly greater in PSA-positive cells.
1951:
Heise C, Sampson-Johannes A, Williams A, Mccormick F, Von Hoff DD, Kirn DH (June 1997). "ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents".
433:
when injected directly into a tumour, and when any resulting fever is not suppressed. Systemic therapy (such as through infusion through an intravenous line) is desirable for treating metastatic disease. It is now marketed under the brand name
1759:
Fernandes MS, Gomes EM, Butcher LD, Hernandez-Alcoceba R, Chang D, Kansopon J, Newman J, Stone MJ, Tong AW (1 August 2009). "Growth
Inhibition of Human Multiple Myeloma Cells by an Oncolytic Adenovirus Carrying the CD40 Ligand Transgene".
610:
gene, it will be prevented from multiplying by the action of the p53 transcription factor. However, if Onyx-015 infects a p53 deficient cell it should be able to survive and replicate, resulting in selective destruction of cancer cells.
2310:
Dyer A, Schoeps B, Frost S, Jakeman P, Scott EM, Freedman J, Jacobus EJ, Seymour LW (2019-01-15). "Antagonism of
Glycolysis and Reductive Carboxylation of Glutamine Potentiates Activity of Oncolytic Adenoviruses in Cancer Cells".
164:
for a cell-surface receptor. The use of adapter molecules has been shown to increase viral transduction. However, adapters add complexity to the system, and the effect of adapter molecule binding on the stability of the virus is
1581:
Ramesh N, Ge Y, Ennist DL, Zhu M, Mina M, Ganesh S, Reddy PS, Yu DC (2006). "CG0070, a
Conditionally Replicating Granulocyte Macrophage Colony-Stimulating Factor–Armed Oncolytic Adenovirus for the Treatment of Bladder Cancer".
914:
Carette JE, Overmeer RM, Schagen FH, Alemany R, Barski OA, Gerritsen WR, Van
Beusechem VW (2004). "Conditionally Replicating Adenoviruses Expressing Short Hairpin RNAs Silence the Expression of a Target Gene in Cancer Cells".
1445:
Hirvinen M, Rajecki M, Kapanen M, Parviainen S, Rouvinen-Lagerström N, Diaconu I, Nokisalmi P, Tenhunen M, Hemminki A, Cerullo V (2015). "Immunological
Effects of a Tumor Necrosis Factor Alpha–Armed Oncolytic Adenovirus".
582:
produced by adenoviruses protect the infected cell by binding to and degrading the p53 transcription factors, preventing it from targeting the cell for apoptosis. This allows the virus to replicate, package its genome,
141:, CAR expression in tumours is extremely variable, leading to resistance to Ad5 infection. Retargeting of Ad5 from CAR, to another receptor that is ubiquitously expressed on cancer cells, may overcome this resistance.
2171:
Freytag SO, Khil M, Stricker H, Peabody J, Menon M, et al. (2002). "Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer".
626:
the comparison of intra-tumoural versus intravenous injection to examine viral replication, viral spread, tumour necrosis and anti-tumoural immune responses (see the EU Clinical Trials
Register for further details).
2693:
Bischoff JR, Kirn DH, Williams A, Heise C, Horn S, Muna M, Ng L, Nye JA, Sampson-Johannes A, Fattaey A, McCormick F (1996). "An Adenovirus Mutant That Replicates Selectively in p53- Deficient Human Tumor Cells".
221:
by placing the early genes under the control of a Cox-2 promoter (adenoviruses have two early genes, E1A and E1B, that are essential for replication). When combined with transductional targeting,
2261:
Dyer A, Di Y, Calderon H, Illingworth S, Kueberuwa G, Tedcastle A, Jakeman P, Chia SL, Brown A, Silva M, Barlow D, Beadle J, Hermiston T, Ferguson D, Champion B, Fisher K, Seymour L (2017).
670:. Further development of Onyx-015 was abandoned in the early 2000s, the exclusive rights being licensed to the Chinese company, Shanghai Sunway Biotech. On November 17, 2005, the Chinese
186:
insertions of up to 100 residues without any negative effects on adenovirus integrity. An RGD motif inserted into the HI loop of the fiber knob protein, shifts specificity toward
494:
monotherapies. The need for increased potency (infectivity and lytic activity) has led to an expanded search involving a larger number of less well studied adenovirus serotypes.
650:
to combat head and neck tumours. Onyx-015 has been extensively tested in clinical trials, with the data indicating that it is safe and selective for cancer. However, limited
225:
showed potential for treatment of Oesophageal Adenocarcinoma. Cox-2 is also a possible tumour-specific promoter candidate for other cancer types, including ovarian cancer.
2538:
Barker DD, Berk AJ (1987). "Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection".
1916:
Barker DD, Berk AJ (1987). "Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection".
519:
that outcome. One particular application of this approach produced ColoAd1, which is a novel Ad11p/Ad3 chimeric Group B oncolytic virus with specificity for human
194:. When combined with a form of non-transductional targeting, these viruses proved to be effective and selective therapeutic agents for Oesophageal Adenocarcinoma.
42:
Of the many different viruses being explored for oncolytic potential, an adenovirus was the first to be approved by a regulatory agency, the genetically modified
678:, an oncolytic adenovirus similar to Onyx-015 (E1B-55K/E3B-deleted), for use in combination with chemotherapy for the treatment of late-stage refractory
1626:
Hemminki A (2010). "Oncolytic Adenovirus Coding for Granulocyte Macrophage Colony-Stimulating Factor Induces Antitumoral Immunity in Cancer Patients".
1113:"Prostate attenuated replication competent adenovirus (ARCA) CN706: A selective cytotoxic for prostate-specific antigen-positive prostate cancer cells"
574:. It blocks cell progression in response to cellular stress or DNA damage. Many viruses replicate by altering the cell cycle and exploiting the same
54:
Adenoviruses have so far been through three generations of development. Some of the strategies for modification of adenoviruses are described below.
1234:"MiR-148a- and miR-216a-regulated Oncolytic Adenoviruses Targeting Pancreatic Tumors Attenuate Tissue Damage Without Perturbation of miRNA Activity"
2202:
Kuhn I, Harden P, Bauzon M, Chartier C, Nye J, Thorne S, Reid T, Ni S, Lieber A, Fisher K, Seymour L, Rubanyi GM, Harkins RN, Hermiston TW (2008).
3031:
130:
46:
strain. It gained regulatory approval in 2005 from China's State Food and Drug Administration (SFDA) for the treatment of head and neck cancer.
66:
by viral proteins interfering with cell cycle proteins. The adenoviral E1A gene is responsible for inactivation of several proteins, including
2263:"Oncolytic Group B Adenovirus Enadenotucirev Mediates Non-apoptotic Cell Death with Membrane Disruption and Release of Inflammatory Mediators"
1388:
890:
750:
1661:
Dias JD, Hemminki O, Diaconu I, Hirvinen M, Bonetti A, Guse K, Escutenaire S, Kanerva A, Pesonen S, Löskog A, Cerullo V, Hemminki A (2012).
249:
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Moon Crompton A, Kirn DH (2007). "From ONYX-015 to Armed Vaccinia Viruses: The Education and Evolution of Oncolytic Virus Development".
1712:"Armed Oncolytic Adenovirus–Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors"
671:
1414:"Targeting Interferon-α Increases Antitumor Efficacy and Reduces Hepatotoxicity of E1A-mutated Spread-enhanced Oncolytic Adenovirus"
1795:
Eriksson E, Milenova I, Wenthe J, Ståhle M, Leja-Jarblad J, Ullenhag G, Dimberg A, Moreno R, Alemany R, Loskog A (1 October 2017).
213:(Cox-2) expression is elevated in a range of cancers, and has low liver expression, making it a suitable tumour-specific promoter.
152:
Bi-specific adapter molecules can be administered along with the virus to redirect viral coat protein tropism. These molecules are
1481:
Bortolanza S, Bunuales M, Otano I, Gonzalez-Aseguinolaza G, Ortiz-De-Solorzano C, Perez D, Prieto J, Hernandez-Alcoceba R (2009).
1144:"Generation of a conditionally replicating adenovirus based on targeted destruction of E1A mRNA by a cell type-specific MicroRNA"
2853:"Translation of targeted oncolytic virotherapeutics from the lab into the clinic, and back again: a high-value iterative loop"
70:, allowing entry into S-phase. The adenovirus E1B55kDa gene cooperates with another adenoviral product, E4ORF6, to inactivate
2988:
206:
This approach takes advantage of deregulated promoter to drive and control the expression of adenoviral genes. For instance,
2808:
Kirn D, Thorne S (2009). "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer".
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This method involves genetically modifying the fiber knob domain of the viral coat protein to alter its specificity. Short
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1797:"Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus"
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590:
This gave rise to the idea that an altered adenovirus could be used to target and eliminate cancer cells.
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3036:
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2952:
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2019:
1969:
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886:
855:
805:
756:
746:
742:
575:
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258:
Another layer of regulation that has emerged to control adenoviral replication is the use of
2942:
2903:
2864:
2817:
2774:
2711:
2647:
2637:
2596:
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To enhance the efficacy, therapeutic transgenes are integrated into oncolytic adenovirus
2707:
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383:
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2652:
2625:
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2574:
2464:
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428:, which is very frequently dysregulated in cancer cells. Despite the promises of early
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126:
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659:
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478:
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2992:
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1007:
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859:
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639:
603:
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424:
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71:
253:
Oncolytic adenovirus controlled by microRNA response element
2575:"Oncolytic Adenovirus: Prospects for Cancer Immunotherapy"
133:(CAR), and the knob domain of the adenovirus coat protein
399:
Targeting costimulatory and Immune Checkpoints on T-cells
129:
cells is initiated by interactions between the cellular
93:
A conditionally replicative adenovirus (CRAd) with a 24
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1911:
1909:
121:The most commonly used group of adenoviruses is
733:Harrington KJ, Pandha H, Vile RG, eds. (2008).
682:. Outside of China, the push to the clinic for
78:. It was initially proposed that an adenovirus
2626:"Oncolytic Adenovirus in Cancer Immunotherapy"
1532:"Oncolytic Adenovirus in Cancer Immunotherapy"
827:
825:
823:
821:
819:
27:varieties have been explored extensively as a
2197:
2195:
1845:Medicina Oral, Patologia Oral y Cirugia Bucal
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1065:
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86:(ONYX-015), could replicate selectively in
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190:, which are frequently over-expressed in
950:
948:
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43:
638:Patents for the therapeutic use of
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587:the cell and spread to new cells.
578:that are altered in cancer cells.
14:
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244:Post-Transcriptional detargeting
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305:Prevent muscle inflammation,
2716:10.1126/science.274.5286.373
2552:10.1016/0042-6822(87)90441-7
2376:10.1016/0168-9525(93)90209-Z
2267:Molecular Therapy Oncolytics
2229:10.1371/journal.pone.0002409
1930:10.1016/0042-6822(87)90441-7
506:currently in development is
502:One non-species C oncolytic
2895:Current Cancer Drug Targets
1381:10.1007/978-1-61779-340-0_3
883:10.1007/978-1-61779-340-0_3
217:is a CRAd targeted against
101:-binding domain of the E1A
82:lacking the E1B55kDa gene,
3063:
2908:10.2174/156800907780058862
2624:Peter M, Kühnel F (2020).
2279:10.1016/j.omto.2016.11.003
418:H101 and the very similar
219:oesophageal adenocarcinoma
192:oesophageal adenocarcinoma
125:5 (Ad5), whose binding to
17:
2592:10.3389/fmicb.2021.707290
2579:Frontiers in Microbiology
2444:British Journal of Cancer
606:cell, with a functioning
200:Transcriptional targeting
171:Coat-protein modification
2064:10.1517/14712598.1.3.525
1801:Clinical Cancer Research
1762:Clinical Cancer Research
1584:Clinical Cancer Research
1287:Clinical Cancer Research
1232:Bofill-De Ros X (2014).
1000:10.2174/1566523043346372
690:mechanism can be found.
516:homologous recombination
514:produced by the initial
289:Prevent liver toxicity,
2643:10.3390/cancers12113354
2438:Ries S, Korn W (2002).
1549:10.3390/cancers12113354
737:Viral therapy of cancer
666:for therapeutic use as
458:genetically engineering
156:that are made up of an
2929:Liu T, Kirn D (2008).
2810:Nature Reviews. Cancer
2456:10.1038/sj.bjc.6600006
2139:10.1038/sj.cgt.7700539
710:Oncolytic herpes virus
368:Arming with Transgenes
254:
2746:US patent 5677178
2052:Expert Opin Biol Ther
1431:10.1038/sj.mt.6300064
680:nasopharyngeal cancer
566:that plays a role in
252:
234:is prostate-specific
18:Further information:
1460:10.1089/hum.2014.069
1160:10.1128/JVI.01608-08
988:Current Gene Therapy
780:Nature Biotechnology
564:transcription factor
2708:1996Sci...274..373B
2501:1992Natur.357...82Y
2220:2008PLoSO...3.2409K
1680:10.1038/gt.2011.176
1154:(22): 11009–11015.
1148:Journal of Virology
1142:Ylösmäki E (2008).
851:10.1093/jnci/djj111
658:when combined with
2995:on 16 October 2006
2948:10.1038/gt.2008.72
2870:10.1038/mt.2008.70
2680:clinicaltrials.gov
2364:Trends in Genetics
2095:Curr Opin Mol Ther
1966:10.1038/nm0697-639
1448:Human Gene Therapy
1342:10.1002/glia.20795
1250:10.1038/mt.2014.98
1038:10.1038/nm0103-135
792:10.1038/nbt0108-37
652:therapeutic effect
562:pathway. p53 is a
485:Directed Evolution
255:
74:, thus preventing
2857:Molecular Therapy
2702:(5286): 373–376.
2676:"CTG Labs - NCBI"
2397:Levine A (1997).
2180:(17): 4968–4976.
1807:(19): 5846–5857.
1768:(15): 4847–4856.
1634:(11): 4297–4309.
1499:10.1038/mt.2009.9
1487:Molecular Therapy
1418:Molecular Therapy
1390:978-1-61779-339-4
1373:Oncolytic Viruses
1293:(16): 5126–5135.
1238:Molecular Therapy
1203:(11): 1278–1283.
1191:Kelly EJ (2008).
892:978-1-61779-339-4
875:Oncolytic Viruses
832:Garber K (2006).
752:978-0-470-01922-1
570:, cell cycle and
365:
364:
146:Adapter molecules
90:deficient cells.
3054:
3005:
3004:
3002:
3000:
2985:
2979:
2978:
2967:
2961:
2960:
2950:
2926:
2920:
2919:
2889:
2883:
2882:
2872:
2863:(6): 1006–1008.
2848:
2842:
2841:
2805:
2799:
2798:
2761:
2755:
2754:
2753:
2749:
2742:
2736:
2735:
2690:
2684:
2683:
2672:
2666:
2665:
2655:
2645:
2621:
2615:
2614:
2604:
2594:
2570:
2564:
2563:
2535:
2529:
2528:
2509:10.1038/357082a0
2484:
2478:
2477:
2467:
2435:
2429:
2428:
2418:
2394:
2388:
2387:
2359:
2353:
2352:
2307:
2301:
2300:
2290:
2258:
2252:
2251:
2241:
2231:
2199:
2190:
2189:
2168:
2162:
2161:
2151:
2141:
2126:Cancer Gene Ther
2117:
2111:
2110:
2090:
2084:
2083:
2047:
2041:
2034:
2028:
2027:
2006:
2000:
1999:
1992:
1986:
1985:
1948:
1942:
1941:
1913:
1904:
1903:
1878:(5803): 1232–5.
1867:
1861:
1860:
1842:
1833:
1827:
1826:
1816:
1792:
1786:
1785:
1756:
1750:
1749:
1739:
1722:(8): 2040–2051.
1707:
1701:
1700:
1682:
1658:
1652:
1651:
1622:
1616:
1615:
1578:
1572:
1571:
1561:
1551:
1527:
1521:
1520:
1510:
1478:
1472:
1471:
1442:
1436:
1435:
1433:
1409:
1403:
1402:
1368:
1362:
1361:
1325:
1319:
1318:
1278:
1272:
1271:
1261:
1244:(9): 1665–1677.
1229:
1223:
1222:
1212:
1188:
1182:
1181:
1171:
1139:
1133:
1132:
1108:
1102:
1101:
1091:
1067:
1058:
1057:
1021:
1012:
1011:
983:
977:
976:
952:
941:
940:
911:
905:
904:
870:
864:
863:
853:
829:
814:
813:
803:
771:
765:
764:
740:
730:
598:, meaning cells
560:tumor suppressor
335:miR-143, miR-145
323:pancreatic tumor
302:miR-133, miR-206
269:Tissue/cell-type
266:
208:Cyclooxygenase-2
139:epithelial cells
97:deletion in the
3062:
3061:
3057:
3056:
3055:
3053:
3052:
3051:
3022:
3021:
3013:
3008:
2998:
2996:
2987:
2986:
2982:
2969:
2968:
2964:
2941:(12): 877–884.
2928:
2927:
2923:
2891:
2890:
2886:
2850:
2849:
2845:
2822:10.1038/nrc2545
2807:
2806:
2802:
2767:Nature Medicine
2763:
2762:
2758:
2751:
2744:
2743:
2739:
2692:
2691:
2687:
2674:
2673:
2669:
2623:
2622:
2618:
2572:
2571:
2567:
2537:
2536:
2532:
2495:(6373): 82–85.
2486:
2485:
2481:
2437:
2436:
2432:
2396:
2395:
2391:
2361:
2360:
2356:
2313:Cancer Research
2309:
2308:
2304:
2260:
2259:
2255:
2201:
2200:
2193:
2170:
2169:
2165:
2132:(12): 979–986.
2119:
2118:
2114:
2092:
2091:
2087:
2049:
2048:
2044:
2040:2005;5:965–976.
2035:
2031:
2018:(22): 6359–66.
2008:
2007:
2003:
1994:
1993:
1989:
1954:Nature Medicine
1950:
1949:
1945:
1915:
1914:
1907:
1869:
1868:
1864:
1840:
1835:
1834:
1830:
1794:
1793:
1789:
1758:
1757:
1753:
1716:Cancer Research
1709:
1708:
1704:
1673:(10): 988–998.
1660:
1659:
1655:
1628:Cancer Research
1624:
1623:
1619:
1580:
1579:
1575:
1529:
1528:
1524:
1480:
1479:
1475:
1444:
1443:
1439:
1411:
1410:
1406:
1391:
1370:
1369:
1365:
1327:
1326:
1322:
1281:Lee CY (2009).
1280:
1279:
1275:
1231:
1230:
1226:
1210:10.1038/nm.1776
1197:Nature Medicine
1190:
1189:
1185:
1141:
1140:
1136:
1123:(13): 2559–63.
1117:Cancer Research
1110:
1109:
1105:
1082:(12): 4319–27.
1076:Cancer Research
1069:
1068:
1061:
1026:Nature Medicine
1023:
1022:
1015:
985:
984:
980:
961:Cancer Research
954:
953:
944:
917:Cancer Research
913:
912:
908:
893:
872:
871:
867:
831:
830:
817:
773:
772:
768:
753:
732:
731:
727:
723:
700:Oncolytic virus
696:
636:
617:
615:Clinical trials
530:
500:
487:
454:oncolytic virus
447:
416:
414:Oncorine (H101)
411:
232:prostate cancer
154:fusion proteins
119:
60:
52:
37:oncolytic virus
35:and also as an
22:
20:Oncolytic virus
12:
11:
5:
3060:
3058:
3050:
3049:
3044:
3039:
3034:
3024:
3023:
3020:
3019:
3012:
3011:External links
3009:
3007:
3006:
2980:
2962:
2921:
2884:
2843:
2800:
2773:(8): 879–885.
2756:
2737:
2685:
2667:
2616:
2565:
2546:(1): 107–121.
2530:
2479:
2430:
2409:(3): 323–331.
2389:
2370:(4): 138–141.
2354:
2319:(2): 331–345.
2302:
2253:
2191:
2163:
2112:
2101:(5): 435–443.
2085:
2058:(3): 525–538.
2042:
2038:Nat Rev Cancer
2029:
2001:
1987:
1960:(6): 639–645.
1943:
1924:(1): 107–121.
1905:
1862:
1828:
1787:
1751:
1702:
1653:
1617:
1590:(1): 305–313.
1573:
1522:
1493:(4): 614–622.
1473:
1454:(3): 134–144.
1437:
1424:(3): 598–607.
1404:
1389:
1363:
1336:(6): 667–679.
1320:
1273:
1224:
1183:
1134:
1103:
1059:
1013:
978:
942:
906:
891:
865:
844:(5): 298–300.
815:
766:
751:
724:
722:
719:
718:
717:
712:
707:
702:
695:
692:
648:5-fluorouracil
635:
628:
616:
613:
529:
526:
499:
496:
486:
483:
446:
439:
415:
412:
410:
407:
402:
401:
391:
390:
380:
379:
363:
362:
360:
353:
350:
346:
345:
343:
340:prostate tumor
336:
333:
329:
328:
326:
319:
316:
312:
311:
309:
303:
300:
296:
295:
293:
291:hepatotoxicity
287:
284:
280:
279:
276:
275:Use of the MRE
273:
272:Enriched miRNA
270:
264:
263:
247:
246:
240:
239:
227:
226:
203:
202:
196:
195:
174:
173:
167:
166:
149:
148:
118:
115:
99:retinoblastoma
68:retinoblastoma
59:
56:
51:
48:
13:
10:
9:
6:
4:
3:
2:
3059:
3048:
3047:Biotechnology
3045:
3043:
3040:
3038:
3035:
3033:
3030:
3029:
3027:
3018:
3015:
3014:
3010:
2994:
2990:
2984:
2981:
2976:
2972:
2966:
2963:
2958:
2954:
2949:
2944:
2940:
2936:
2932:
2925:
2922:
2917:
2913:
2909:
2905:
2901:
2897:
2896:
2888:
2885:
2880:
2876:
2871:
2866:
2862:
2858:
2854:
2847:
2844:
2839:
2835:
2831:
2827:
2823:
2819:
2815:
2811:
2804:
2801:
2796:
2792:
2788:
2784:
2780:
2779:10.1038/78638
2776:
2772:
2768:
2760:
2757:
2747:
2741:
2738:
2733:
2729:
2725:
2721:
2717:
2713:
2709:
2705:
2701:
2697:
2689:
2686:
2681:
2677:
2671:
2668:
2663:
2659:
2654:
2649:
2644:
2639:
2635:
2631:
2627:
2620:
2617:
2612:
2608:
2603:
2598:
2593:
2588:
2584:
2580:
2576:
2569:
2566:
2561:
2557:
2553:
2549:
2545:
2541:
2534:
2531:
2526:
2522:
2518:
2514:
2510:
2506:
2502:
2498:
2494:
2490:
2483:
2480:
2475:
2471:
2466:
2461:
2457:
2453:
2449:
2445:
2441:
2434:
2431:
2426:
2422:
2417:
2412:
2408:
2404:
2400:
2393:
2390:
2385:
2381:
2377:
2373:
2369:
2365:
2358:
2355:
2350:
2346:
2342:
2338:
2334:
2330:
2326:
2322:
2318:
2314:
2306:
2303:
2298:
2294:
2289:
2284:
2280:
2276:
2272:
2268:
2264:
2257:
2254:
2249:
2245:
2240:
2235:
2230:
2225:
2221:
2217:
2213:
2209:
2205:
2198:
2196:
2192:
2187:
2183:
2179:
2175:
2167:
2164:
2159:
2155:
2150:
2145:
2140:
2135:
2131:
2127:
2123:
2116:
2113:
2108:
2104:
2100:
2096:
2089:
2086:
2081:
2077:
2073:
2069:
2065:
2061:
2057:
2053:
2046:
2043:
2039:
2033:
2030:
2025:
2021:
2017:
2013:
2005:
2002:
1997:
1991:
1988:
1983:
1979:
1975:
1971:
1967:
1963:
1959:
1955:
1947:
1944:
1939:
1935:
1931:
1927:
1923:
1919:
1912:
1910:
1906:
1901:
1897:
1893:
1889:
1885:
1881:
1877:
1873:
1866:
1863:
1858:
1854:
1851:(1): E15–21.
1850:
1846:
1839:
1832:
1829:
1824:
1820:
1815:
1810:
1806:
1802:
1798:
1791:
1788:
1783:
1779:
1775:
1771:
1767:
1763:
1755:
1752:
1747:
1743:
1738:
1733:
1729:
1725:
1721:
1717:
1713:
1706:
1703:
1698:
1694:
1690:
1686:
1681:
1676:
1672:
1668:
1664:
1657:
1654:
1649:
1645:
1641:
1637:
1633:
1629:
1621:
1618:
1613:
1609:
1605:
1601:
1597:
1593:
1589:
1585:
1577:
1574:
1569:
1565:
1560:
1555:
1550:
1545:
1541:
1537:
1533:
1526:
1523:
1518:
1514:
1509:
1504:
1500:
1496:
1492:
1488:
1484:
1477:
1474:
1469:
1465:
1461:
1457:
1453:
1449:
1441:
1438:
1432:
1427:
1423:
1419:
1415:
1408:
1405:
1400:
1396:
1392:
1386:
1382:
1378:
1374:
1367:
1364:
1359:
1355:
1351:
1347:
1343:
1339:
1335:
1331:
1324:
1321:
1316:
1312:
1308:
1304:
1300:
1296:
1292:
1288:
1284:
1277:
1274:
1269:
1265:
1260:
1255:
1251:
1247:
1243:
1239:
1235:
1228:
1225:
1220:
1216:
1211:
1206:
1202:
1198:
1194:
1187:
1184:
1179:
1175:
1170:
1165:
1161:
1157:
1153:
1149:
1145:
1138:
1135:
1130:
1126:
1122:
1118:
1114:
1107:
1104:
1099:
1095:
1090:
1085:
1081:
1077:
1073:
1066:
1064:
1060:
1055:
1051:
1047:
1043:
1039:
1035:
1031:
1027:
1020:
1018:
1014:
1009:
1005:
1001:
997:
994:(3): 337–46.
993:
989:
982:
979:
974:
970:
967:(2): 325–30.
966:
962:
958:
951:
949:
947:
943:
938:
934:
930:
926:
923:(8): 2663–7.
922:
918:
910:
907:
902:
898:
894:
888:
884:
880:
876:
869:
866:
861:
857:
852:
847:
843:
839:
835:
828:
826:
824:
822:
820:
816:
811:
807:
802:
797:
793:
789:
785:
781:
777:
770:
767:
762:
758:
754:
748:
744:
739:
738:
729:
726:
720:
716:
713:
711:
708:
706:
705:Oncolytic AAV
703:
701:
698:
697:
693:
691:
689:
685:
681:
677:
673:
669:
665:
661:
657:
653:
649:
645:
641:
633:
629:
627:
624:
620:
614:
612:
609:
605:
601:
597:
593:
588:
586:
581:
577:
573:
569:
565:
561:
558:
554:
550:
546:
542:
538:
534:
527:
525:
522:
517:
513:
509:
505:
497:
495:
492:
484:
482:
480:
476:
473:
469:
468:
463:
459:
455:
451:
444:
440:
438:
436:
431:
427:
426:
421:
413:
408:
406:
400:
397:
396:
395:
389:
386:
385:
384:
378:
375:
374:
373:
370:
369:
361:
358:
354:
351:
348:
347:
344:
341:
337:
334:
331:
330:
327:
324:
320:
317:
314:
313:
310:
308:
304:
301:
298:
297:
294:
292:
288:
285:
282:
281:
277:
274:
271:
268:
267:
261:
257:
256:
251:
245:
242:
241:
237:
233:
229:
228:
224:
220:
216:
212:
209:
205:
204:
201:
198:
197:
193:
189:
184:
181:added to the
180:
176:
175:
172:
169:
168:
163:
159:
155:
151:
150:
147:
144:
143:
142:
140:
136:
132:
128:
124:
116:
114:
112:
108:
104:
100:
96:
91:
89:
85:
81:
77:
73:
69:
65:
57:
55:
49:
47:
45:
40:
38:
34:
30:
26:
21:
16:
3037:Adenoviridae
2997:. Retrieved
2993:the original
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2974:
2965:
2938:
2935:Gene Therapy
2934:
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2902:(2): 133–9.
2899:
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2856:
2846:
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2051:
2045:
2037:
2032:
2015:
2011:
2004:
1990:
1957:
1953:
1946:
1921:
1917:
1875:
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1848:
1844:
1831:
1804:
1800:
1790:
1765:
1761:
1754:
1719:
1715:
1705:
1670:
1667:Gene Therapy
1666:
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1631:
1627:
1620:
1587:
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1542:(11): 3354.
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1200:
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1186:
1151:
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1032:(1): 135–9.
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991:
987:
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960:
920:
916:
909:
874:
868:
841:
837:
786:(1): 37–53.
783:
779:
769:
736:
728:
687:
683:
667:
663:
660:chemotherapy
655:
637:
631:
621:
618:
607:
589:
580:E1B proteins
551:control and
547:involved in
531:
521:colon cancer
512:biodiversity
501:
488:
479:cancer cells
465:
449:
448:
442:
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429:
423:
417:
403:
398:
394:responses ,
392:
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199:
170:
145:
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110:
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92:
83:
61:
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41:
33:gene therapy
29:viral vector
23:
15:
3042:Virotherapy
2450:(1): 5–11.
715:Virotherapy
596:knocked out
477:-deficient
456:created by
278:References
58:Attenuation
3026:Categories
2585:: 707290.
2174:Cancer Res
2012:Cancer Res
1996:"Facebook"
721:References
634:1520)/H101
630:ONYX-015 (
572:DNA repair
549:cell cycle
528:Background
504:adenovirus
462:adenovirus
441:Onyx-015 (
223:AdCox2Lluc
215:AdCox2Lluc
183:C-terminal
165:uncertain.
107:Ad5- Δ24E3
25:Adenovirus
2333:1538-7445
2273:: 18–30.
1900:142897522
761:183831087
674:approved
644:cisplatin
568:apoptosis
553:apoptosis
541:mutations
491:oncolytic
467:E1B-55kDa
359:targeting
357:astrocyte
342:targeting
325:targeting
260:microRNAs
188:integrins
117:Targeting
111:Ad5-Δ24E3
95:base pair
76:apoptosis
2975:Medscape
2957:18418413
2916:17346104
2879:18500240
2838:20344137
2830:19104515
2787:10932224
2732:27240699
2662:33202717
2611:34367111
2540:Virology
2474:11857003
2349:54162449
2341:30487139
2297:28345021
2248:18560559
2208:PLOS ONE
2186:12208748
2158:12522437
2107:12435044
2080:39588407
2072:11727523
2024:11103798
1918:Virology
1892:17124300
1857:18167474
1823:28536305
1782:19622582
1746:28235763
1689:22071969
1648:20484030
1604:16397056
1568:33202717
1517:19223865
1468:25557131
1399:21948467
1350:18942755
1307:19671871
1268:24895996
1219:18953352
1178:18799589
1098:15205347
1046:12514727
1008:15384947
937:15087375
901:21948467
860:16507823
810:18183014
694:See also
684:ONYX-015
664:ONYX-015
656:ONYX-015
640:ONYX-015
600:infected
592:Onyx-015
576:pathways
535:form in
450:Onyx-015
435:Oncorine
420:Onyx-015
409:Examples
355:Promote
338:Promote
332:Prostate
321:Promote
318:miR-148a
315:Pancreas
307:myositis
179:peptides
158:antibody
123:serotype
2999:25 July
2795:3199209
2724:8832876
2704:Bibcode
2696:Science
2653:7697649
2630:Cancers
2602:8334181
2560:2949421
2525:4338026
2517:1533443
2497:Bibcode
2465:2746528
2425:9039259
2384:8516849
2288:5363721
2239:2423470
2216:Bibcode
2149:7091735
1982:7418713
1974:9176490
1938:2949421
1872:Science
1737:5392365
1697:6824405
1612:2071049
1559:7697649
1536:Cancers
1508:2835109
1358:5006543
1259:4435498
1169:2573287
1129:9205053
1054:5381985
973:9927041
801:7096943
623:ColoAd1
533:Tumours
508:ColoAd1
498:ColoAd1
430:in vivo
352:miR-124
286:miR-122
236:antigen
103:protein
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349:Neuron
299:Muscle
211:enzyme
162:ligand
135:trimer
84:dl1520
80:mutant
2834:S2CID
2791:S2CID
2728:S2CID
2521:S2CID
2345:S2CID
2076:S2CID
1978:S2CID
1896:S2CID
1841:(PDF)
1693:S2CID
1608:S2CID
1354:S2CID
1311:S2CID
1050:S2CID
745:–13.
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539:when
537:cells
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283:Liver
3001:2006
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2875:PMID
2826:PMID
2783:PMID
2720:PMID
2658:PMID
2607:PMID
2556:PMID
2513:PMID
2470:PMID
2421:PMID
2403:Cell
2380:PMID
2337:PMID
2329:ISSN
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2244:PMID
2182:PMID
2154:PMID
2103:PMID
2068:PMID
2020:PMID
1970:PMID
1934:PMID
1888:PMID
1853:PMID
1819:PMID
1778:PMID
1742:PMID
1685:PMID
1644:PMID
1600:PMID
1564:PMID
1513:PMID
1464:PMID
1395:PMID
1385:ISBN
1346:PMID
1330:Glia
1303:PMID
1264:PMID
1215:PMID
1174:PMID
1125:PMID
1094:PMID
1042:PMID
1004:PMID
969:PMID
933:PMID
897:PMID
887:ISBN
856:PMID
806:PMID
757:OCLC
747:ISBN
688:real
676:H101
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585:lyse
472:lyse
127:host
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2865:doi
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