**Author details**

caused antitumor responses in preclinical models and even some responses in earlier clinical trials. In a small clinical trial, an attenuated vaccinia vector carrying IL-2 and MUC1 has been found effective in a small group of patients with advanced prostatic cancer [199]. Likewise, a vector vaccine of canary poxvirus encoding B7.1 and CEA has been tested in a group of patients with epithelial tumors [200]. Hundreds of different DNA vaccines have been tested in clinical

Gene therapy vectors have also been used to transduce either autologous tumor cells or dendritic cells. In the earlier studies, irradiated autologous tumor cells transduced to express immunostimulatory molecules have been tested. In a syngeneic colon cancer model, the subcutaneous injection of CT26 colon cancer cells transduced with an adenoviral vector carrying GM-CSF gene has eliminated both the established tumors and prevented the growth of new tumor nodules when rechallenged with tumor cells [201]. Later on, this strategy has also been tested in human tumors. Autologous tumors transduced with GVAX, an adenovirus carrying GM-CSF, have induced tumor-specific immunity in a variety of tumors, including melanoma, prostate, and lung cancers [203]. Although a slight increase in overall survival has

The ex vivo transduction of dendritic cells with gene therapy vectors carrying either immunostimulatory genes or TAAs is another promising strategy. When injected subcuta‐ neously, the dendritic cells exposed to vectors migrate to the lymph nodes where they prime cytotoxic T cells and induce a strong immune response. A number of vectors have been designed to activate dendritic cells for the past two decades. We have tested the use of ex vivo transduced dendritic cells with an adenoviral vector carrying a fusion protein of CD40L and MUC1 in a syngeneic mouse tumor model [205]. The intratumoral injec‐ tion of activated dendritic cells induced a potent tumor-specific T-cell response. Further‐ more, the combination of suicide gene therapy of a CD/5FU system and activated dendritic cells caused a more potent immune response and increased tumor response [205]. Like‐ wise, retroviral vectors and lentiviral vectors are both used to transduce dendritic cells [206]. A dendritic cell vaccine based on the ex vivo activation of mononuclear antigen presenting cells by a fusion protein consisting prostatic acid phosphatase and GM-CSF has extended the progression-free survival of patients with advanced prostatic cancer and

Recently, an adoptive therapy of cancer using genetically modified T cells armed with chimeric antigen receptors (CAR) has gained great popularity with the announcement of success in advanced malignancies [208]. CAR is a fusion receptor of an antibody-derived targeting domain and T-cell signaling domain and expressed on T cells by a retroviral vector [209]. CARs target antigens, including proteins, carbohydrates, and glycolipids without antigen processing or HLA recognition. They can be generated in significant quantities ex vivo and used with the minimal risk of autoimmunity or graft versus host disease [210,211]. However, because of the severe side effects, the most troublesome being cytokine-release syndrome, researchers try to

obtain better CAR T cells with further refinement of receptor and better targets [212].

trials so far [202]. However, no DNA vaccine is available in the market.

18 Gene Therapy - Principles and Challenges

been reported in those trials, no significant tumor responses observed [203,204].

approved by FDA in 2010 (Provenge®, Dendreon, USA) [207].

Hakan Akbulut\* , Muge Ocal and Gizem Sonugur

\*Address all correspondence to: akbulut@medicine.ankara.edu.tr

Gene Therapy Research Unit, Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey

### **References**


[17] Kircheis R, Schuller S, Brunner S, Ogris M, Heider KH, Zauner W, Wagner E. Polyca‐ tion-based DNA complexes for tumor-targeted gene delivery in vivo. J Gene Med 1999;1:111–120.

[4] Zhang J, Hochwald SN. Targeting receptor tyrosine kinases in solid tumors. Surg

[5] Cheng L, Ren W, Xie L, Li M, Liu J, Hu J, Liu BR, Qian XP. Anti-EGFR MoAb treat‐ ment in colorectal cancer: limitations, controversies, and contradictories. Cancer Che‐

[6] Naidoo J, Page DB, Wolchok JD. Immune checkpoint blockade. Hematol Oncol Clin

[7] Frohlich MW. Sipuleucel-T for the treatment of advanced prostate cancer. Semin On‐

[8] Hong B, van den Heuvel AP, Prabhu VV, Zhang S, El-Deiry WS. Targeting tumor suppressor p53 for cancer therapy: strategies, challenges and opportunities. Curr

[9] Pagliarini R, Shao W, Sellers WR. Oncogene addiction: pathways of therapeutic re‐ sponse, resistance, and road maps toward a cure. EMBO Rep 2015;16:280–296.

[10] Katoh M. Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular

[11] Low D, Parker SE, Latimer T, Abai AM, Kuwahara-Rundell A, Doh SG, Yang ZY, La‐ face D, Gromkowski SH, Nabel GJ, Manthorpe M, Norman J. Cancer gene therapy using plasmid DNA: pharmacokinetic study of DNA following injection in mice.

[12] Legendre JY, Szoka F Jr. Delivery of plasmid DNA into mammalian cell lines using pH-sensitive liposomes: comparison with cationic liposomes. Pharm Res

[13] Paul FW, Dutzar B, Stayton PS, Hoffman A, Anklesiaria P, Harvie P. Poly propylacrylic acid (PPAA) functions as an endosomal escape agent synergistically enhanc‐ ing the transfection potency of folate targeted cationic–lipid–protamine–DNA (LPD)

[14] Bruckheimer EM, Harvie P, Orthel J, Dutzar B, Furstoss K, Mebel E, Anklesaria P, Paul R. In vivo efficacy of folate-targeted lipid–protamine–DNA (LPD-PEG-Folate) complexes in an immunocompetent sybgeneic model for breast adenocarcinoma.

[15] Bailey AL, Sullivan SM. Efficient encapsulation of DNA plasmids in small neutral liposomes induced by ethanol and calcium. Biochim Biophys 2000;1468:239–252. [16] De Smedt Sc, Demeester J, Hennink WE. Cationic polymer based gene delivery sys‐

miRNAs and signaling networks (Review). Int J Mol Med 2013;32:763–7.

Oncol Clin N Am 2013;22:685–703.

mother Pharmacol 2014;74:1–13.

North Am 2014;28:585–600.

Drug Targets 2014;15:80–9.

Hum Gene Ther 1995;6:53–564.

complexes. Mol Ther 2003;7:208.

tems. Pharm Res 2000;17:113–126.

1992;9:1235–1242.

Mol Ther 2003;7:129.

col 2012;39:245–52.

20 Gene Therapy - Principles and Challenges


[46] Vile RG, Russel S, Lemoine N. Cancer gene therapy: hard lessons and new courses. Gene Ther 2000;7:2–8.

[31] Kasala D, Choi JW, Kim SW, Yun CO. Utilizing adenovirus vectors for gene delivery

[32] Lerch TF, Xie Q, Chapman MS. The structure of adeno-associated virus serotype 3B (AAV-3B): insights into receptor binding and immune evasion. Virology 2010;403[1]:

[33] Luo J, Luo Y, Sun J, Zhou Y, Zhang Y, Yang X. Adeno-associated virus-mediated can‐

[34] Dunbar CE, Emmons RV. Gene transfer into hematopoietic progenitor and stem

[35] Carruthers KH, Metzger G, During MJ, Muravlev A, Wang C, Kocak E. Gene-direct‐ ed enzyme prodrug therapy for localized chemotherapeutics in allograft and xeno‐

[36] Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene

[37] Airenne KJ, Hu Y-C, Kost TA, Smith RH, Kotin RM, Ono C, Matsuura Y, Wang S, Yla-Herttsala S. Baculovirus: an insect-derived vector for diverse gene transfer appli‐

[39] Luo WY, Shih YS, Hung CL, Lo KW, Chiang CS, Lo WH, Huang SF, Wang SC, Yu CF, Chien CH, Hu YC. Development of the hybrid sleeping beauty: baculovirus vec‐ tor for sustained gene expression and cancer therapy. Gene Ther 2012;19: 844–851.

[40] van Oers MM, Pijlman GP, Vlak JM. Thirty years of baculovirus–insect cell protein expression: from dark horse to mainstream technology. J Gen Virol 2015;96:6–23.

[41] Baldo A, van den Akker E, Bergmans HE, Lim F, Pauwels K. General considerations on the biosafety of virus-derived vectors used in gene therapy and vaccination. Curr

[42] Manservigi R, Argnani R, Marconi P. HSV recombinant vectors for gene therapy.

[43] Zhang G, Jin G, Nie X, Mi R, Zhu G, Jia W, Liu F. Enhanced antitumor efficacy of an oncolytic herpes simplex virus expressing an endostatin–angiostatin fusion gene in

[44] Moss B. Genetically engineered poxviruses for recombinant gene expression, vacci‐

[45] Gómez CE, Nájera JL, Krupa M, Esteban M. The Poxvirus vectors MVA and NYVAC as gene delivery systems for vaccination against infectious diseases and cancer. Curr

human glioblastoma stem cell xenografts. PLoS One 2014;9:e95872.

nation, and safety. Proc Natl Acad Sci U S A 1996; 93:11341–11348.

[38] Hu Y-C. Baculovirus vectors for gene therapy. Adv Virus Res 2006;68:287–320.

in cancer. Expert Opin Drug Deliv 2014;11:379–92.

cer gene therapy: current status. Cancer Lett 2015;356:347–56.

cells: progress and problems. Stem Cells 1994;12:563–76.

graft tumor models. Cancer Gene Ther 2014;21:434–40.

therapy. Nat Rev Genet 2014;15:445–451.

cations. Mol Ther 2013;21:739–749.

Gene Ther 2013;13:385–394.

Open Virol J 2010;4:123–156.

Gene Ther 2008;8:97–120.

26–36.

22 Gene Therapy - Principles and Challenges


cific for small cell lung cancer cells using a Myc-Max binding motif. Int J Cancer 2001;91:851–6.

[69] Latham JP, Searle PF, Mautner V, James ND. Prostate specificantigen promoter/ enhancer driven gene therapy for prostate cancer: construction and testing of a tissue specific adenovirus vector. Cancer Res 2000;60:334–341.

[58] Vasey PA, Shulman LN, Campos S, Davis J, Gore M, Johnston S, Kirn DH, O'Neill V, Siddiqui N, Seiden MV, Kaye SB. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin

[59] Li L, Liu RY, Huang JL, Liu QC, Li Y, Wu PH, Zeng YX, Huang W. Adenovirusmediated intra tumoral delivery of the human endostatin gene inhibits tumor

[60] Markert JM, Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, Palmer CA, Feigenbaum F, Tornatore C, Tufaro F, Martuza RL. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a

[61] Rampling R, Cruickshank G, Papanastassiou V, Nicoll J, Hadley D, Brennan D,Petty R, MacLean A, Harland J, McKie E, Mabbs R, Brown M. Toxicity evaluation of repli‐ cation-competent herpes simplex virus (ICP34.5 null mutant 1716] in patients with

[62] Das SK, Sarkar S, Dash R, Dent P, Wang XY, Sarkar D, Fisher PB. Cancer terminator viruses and approaches for enhancing therapeutic outcomes. Adv Cancer Res

[63] Dorer DE, Nettelbeck DM. Targeting cancer by transcriptional control in cancer gene

[64] Osaki T, Tanio Y, Tachibana I, Hosoe S, Kumagal T, Kawase I, Oikawa S, Kishimoto T. Gene therapy for carcinoembryonic antigen-producing human lung cancer cels by cell type-specific expression of herpes simplex virus thymidine kinase gene. Cancer

[65] Takahashi M, Sato T, Sagawa T, Lu Y, Sato Y, Iyama S, Yamada Y, Fukaura J, Takaha‐ shi S, Miyanishi K, Yamashita T, Sasaki K, Kogawa K, Hamada H, Kato J, Niitsu Y. E1B-55K-deleted adenovirus expressing E1A-13S by AFP-enhancer/promoter is capa‐ ble of highly specific replication in AFP-producing hepatocellular carcinoma and

[66] Gupta VK, Park JO, Kurihara T, Koons A, Mauceri HJ, Jaskowiak NT, Kufe DW, Weichselbaum RR, Posner MC. Selective gene expression using a DF3/MUC1 pro‐ moter in a human esophageal adenocarcinoma model. Gene Ther 2003;10:206–12.

[67] Pandha HS, Martin L-A, Rigg A, Hurst HC, Stamp GWH, Sikora K, Lemoine NR. Ge‐ netic prodrug activation therapy for breast cancer: a phase I clinical trial of c-erbB2

[68] Nishino K, Osaki T, Kumagai T, Kijima T, Tachibana I, Goto H, Arai T, Kimura H, Funakoshi T, Takeda Y, Tanio Y, Hayashi S. Adenovirus-mediated gene therapy spe‐

therapy and viral oncolysis. Adv Drug Deliv Rev 2009;61:554–71.

eradication of established tumor. Mol Ther 2002;5:627–34.

directed suicide gene expression. J Clin Oncol 1999;17:2180–2189.

growth in nasopharyngeal carcinoma. Int J Cancer 2006;118:2064–71.

recurrent malignant glioma. Gene Ther 2000;7:859–866.

Oncol 2002;20:1562–9.

24 Gene Therapy - Principles and Challenges

2012;115:1–38.

Res 1994;54:5258–5261.

phase I trial. Gene Ther 2000;7:1–4.


[94] Kasahara N, Dozy AM, Kan YW. Tissue specific targeting of retroviral vectors through ligand-receptor interactions. Science 1994;266:1373–1376.

[80] Tsihlias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-de‐ pendent kinase inhibitors in human cancer. Annu Rev Med 1999;50:401–423.

[81] Naruse I, Hashiro H, Doboushi K, Minato K, Saito R, Mori M. Over-expression of p27 (kip1] induces growth arrest and apoptosis mediated by changes of Rb expression in

[82] Yang CT, You L, Yeh CC, Chang JWC, Zhang F, McCormick F, Jablons DM. Adeno‐ virus-mediated p14 (ARF) gene transfer in human mesothelioma cells. J Natl Cancer

[83] Nettelbeck DM, Zwicker J, Lucibello FC, Gross C, Liu N, Brusselbach S, Muller R. Cell cycle regulated promoters for the targeting of tumor endothelium. Adv Exp

[84] Kimchi-Sarfaty C, Gottesman MM. SV40 pseudovirions as highly efficient vectors for gene transfer and their potential application in cancer therapy. Curr Pharm Biotech‐

[85] Kursa M, Walker GF, Roessler V, Ogris M, Roedl W, Kircheis R, Wagner E. Novel shielded transferrin-polyethylene glycol-polyethynilemine/DNA complexes for sys‐

[86] Liu X, Tian P, Yu Y, Yao M, Cao X, Gu J. Enhanced antitumor effect of EGF R target‐ ed p21WAF-1 and GM-CSF gene transfer in the established murine hepatoma by per‐

[87] Suzuki M, Takayanagi A, Shimizu N. Recombinant single-chain antibodies with vari‐ ous oligopeptide tails for targeted gene delivery. Gene Ther 2003;10:781–88.

[88] Davis ME. Non-viral gene delivery systems. Curr Opin Biotechnol 2002;13:128–131.

[89] Neves C, Escriov V, Byk G, Schermann P, Wils P. Intracellular fate and nuclear tar‐

[90] Harriton-Gazal E, Feder R, Mor A, Graessmann A, Brack-Werner R, Jons D, Gilon C, Loyter A. Targeting of non-karyophilic cell-permeable peptides into the nuclei of in‐ tact cells by covalently attached nuclear localization signals. Biochemistry

[91] Ogris M, Carlisle RC, Bettinger T, Seymour LW. Mellitin enables efficient vesicular escape and enhanced nuclear access of non-viral gene delivery vectors. J Biol Chem

[92] Logg R, Tai CK, Logg A, Anderson WF, Kasahara N. A uniquely stable replicationcompetent retrovirus vector achieves efficient gene delivery in vitro and in solid tu‐

[93] Martin F, Chowdrhury S, Neil SJ, Chester KA, Gosset F-L, Collins MK. Targeted ret‐ roviral infection of tumor celss by receptor cooperation. J Virol 2003;77:2753–2756.

temic tumor-targeted gene transfer. Bioconjug Chem 2003;14 :222–231.

itumoral injection. Cancer Gene Ther 2002;9:100–108.

geting of plasmid DNA. Cell Biol Toxicol 1999;15:193–202.

lung cancer cell lines. Int J Cancer 2000;88:377–83.

Inst 2000;92:636–641.

26 Gene Therapy - Principles and Challenges

nol 2004;5:451–8.

2002;41:9208–9214.

2001;276:47550–47555.

mors. Hum Gene Ther 2001;12:921–932.

Med Biol 1998;451:437–40.


[118] Sun HX, He HW, Zhang SH, Liu TG, Ren KH, He QY, Shao RG. Suppression of N-Ras by shRNA-expressing plasmid increases sensitivity of HepG2 cells to vincristineinduced growth inhibition. Cancer Gene Ther 209;16:693- 702.

[107] Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G. Rescue of mu‐ tants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc Natl

[108] Oshima Y, Sasaki Y, Negishi H, Idogawa M, Toyota M, Yamashita T, Wada T, Na‐ goya S, Kawaguchi S, Yamashita T, Tokino T. Antitumor effect of adenovirus-medi‐ ated p53 family gene transfer on osteosarcoma cell lines. Cancer Biol Ther

[109] Das S, Nama S, Antony S, Somasundaram K. p73 β-expressing recombinant adenovi‐

[110] Knudsen KE, Weber E, Arden KC, Cavenee WK, Feramisco JR, Knudsen ES. The reti‐ noblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death. Onco‐

[111] Liu F, Li Q, Zhang P, Chen F, Cheng Y. Role of adenovirus-mediated retinoblastoma 94 in the treatment of human non-small cell lung cancer. Mol Med Rep 2015;11:3349–

[112] Macnab SA, Turrell SJ, Carr IM, Markham AF, Coletta PL, Whitehouse A. Herpesvi‐ rus saimiri-mediated delivery of the adenomatous polyposis coli tumour suppressor gene reduces proliferation of colorectal cancer cells. Int J Oncol 2011; 39:1173–1181.

[113] Tait DL, Jensen RA, Holt JT, Johnson DH, Gralow J, King MC. Gene therapy for

[114] Farooqi AA, Rehman ZU, Muntane J. Antisense therapeutics in oncology: current sta‐

[115] Bedikian AY, Garbe C, Conry R, Lebbe C, Grob JJ; Genasense Melanoma Study Group. Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low-normal serum

lactate dehydrogenase: 'The AGENDA trial'. Melanoma Res 2014;24:237–243. [116] O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludar‐ abine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol

[117] Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S. Phase III randomised study of dexa‐ methasone with or without oblimersen sodium for patients with advanced multiple

breast and ovarian cancer with BRCA1. Breast Dis 1998;10:89–98.

tus. Onco Targets Ther 2014;3:2035–42.

myeloma. Leuk Lymphoma 2009;50:559–65.

rus: a potential anticancer agent. Cancer Gene Ther 2005;12:417–426.

Acad Sci U S A 2003;100:13303–7.

2007;6:1058–66.

28 Gene Therapy - Principles and Challenges

gene 1999;18: 5239–45.

3353.

2008;26:820.


midine kinase-based gene therapy in advanced hepatocellular carcinoma. Cancer Gene Ther 2010;17:837–43.


esis and chemotherapy by endostatin–cytosine deaminase– uracil phosphoribosyl‐ transferase. Mol Cancer Ther 2011;10:1327–1336.

[142] Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: har‐ nessing the T cell response. Nat Rev Immunol 2012;12:269–281.

midine kinase-based gene therapy in advanced hepatocellular carcinoma. Cancer

[131] Zhang J, Wei F, Wang H, Li H, Qiu M, Ren P, Chen X, Huang Q. Potent anti-tumor activity of telomerase-dependent and HSVTK armed oncolytic adenovirus for non-

[132] Miletic H, Fischer YH, Giroglou T, Rueger MA, Winkeler A, Li H, Himmelreich U, Stenzel W, Jacobs AH, von Laer D. Normal brain cells contribute to the bystander ef‐ fect in suicide gene therapy of malignant glioma. Clin Cancer Res 2007;13:6761–6768.

[133] Blumenthal M, Skelton D, Pepper KA, Jahn T, Methangkool E, Kohn DB. Effective suicide gene therapy for leukemia in a model of insertional oncogenesis in mice. Mol

[134] Beltinger C, Fulda S, Kammertoens T, Meyer E, Uckert W, Debatin KM. Herpes sim‐ plex virus thymidine kinase/ganciclovir induced apoptosis involves ligand inde‐ pendent death receptor aggregation and activation of cas- pases. Proc Natl Acad Sci

[135] Gadi VK, Alexander SD, Kudlow JE, Allan P, Parker WB, Sorscher EJ. In vivo sensiti‐ zation of ovarian tumors to chemotherapy by expression of E. coli purine nucleoside

[136] Karle P, Renner M, Salmons B, Günzburg WH. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther 2001;8:

[137] Hamstra DA, Pagé M, Maybaum J, Rehemtulla A. Expression of endogenously acti‐ vated secreted or cell surface carboxypeptidase A sensitizes tumor cells to methotrex‐

[138] Ambade AV, Joshi GV, Mulherkar R. Effect of suicide gene therapy in combination with immunotherapy on antitumour immune response & tumour regression in a xenograft mouse model for head & neck squamous cell carcinoma. Indian J Med Res

[139] Cao X, Huang X, Ju DW, Zhang W, Hamada H, Wang J. Enhanced antitumoral effect of adenovirus-mediated cytosine deaminase gene therapy by induction of antigenpresenting cells through stem cell factor/granulocyte-macrophage colony-stimulating

[140] Khatri A, Husaini Y, Ow K, Chapman J, Russell PJ.Cytosine deaminase-uracil phos‐ phoribosyltransferase and interleukin (IL)-12 and IL-18: a multimodal anticancer in‐ terface marked by specific modulation in serum cytokines. Clin Cancer Res

[141] Chen CT, Yamaguchi H, Lee HJ, Du Y, Lee HH, Xia W, Yu WH, Hsu JL, Yen CJ, Sun HL, Wang Y, Yeh ET, Hortobagyi GN, Hung MC. Dual targeting of tumor angiogen‐

phosphorylase in a small fraction of cells. Gene Ther 2000;20:1738–1743.

ate-alpha-peptide prodrugs. Cancer Res 2000;60:657–665.

factor gene transfer. Cancer Gene Ther 2000;7:177–186.

small cell lung cancer in vitro and in vivo. J Exp Clin Cancer Res 2010;29:52.

Gene Ther 2010;17:837–43.

30 Gene Therapy - Principles and Challenges

Ther 2007;15:183–192.

U S A 1999;96:8699–704.

220–30.

2010;312:415–422.

2009;15:2323–2334.


[165] Maxwell IH, Terrel KL, Maxwell F. Autonomous parvovirus vectors. Methods 2002;28:168–181.

[153] Vasey PA, Schulman LN, Campos S, Davis J, Gore M, Johnston S, Kirn DH, O'Neill V, Siddiqui N, Seiden MV, Kaye SB. Phase I trial of intraperitoneal injection of the E1B-55kd-gene deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 ev‐ ery 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin On‐

[154] Fueyo J, Gomez-Manzano C, Alemany R, Lee P, McDonnel T, Mitliangel P, Shi YX, Levin VA, Yung WK, Kyritsis AP. A mutant oncolytic adenovirus targeting the Rb

[155] Heise C, Hermiston T, Johnson L, Brooks G, Sampson-Johannes A, Williams A, Haw‐ kins L, Kirn D. An adenovirus E1A mutant that demonstrates potent and selective

[156] Rodriguez R, Schuer ER, Yeong L, Henderson GA, Simons JW, Henderson DR. Pros‐ tate attenuated replication competent adenovirus (ARCA) CN706 a selective cytotox‐ ic for prostate specific antigen postive prostate cancer cells. Cancer Res 1997;57:2559–

[157] Hallenbeck PL, Chang YN, Hay C, Golightly D, Stewart D, Lin J, Phipps S, Chiang YL. A novel tumor-specific replication restricted adenoviral vector for gene therapy

[158] Brunori M, Malerba M, Kashiwasaki H, Iggo R. Replicating adenoviruses that target tumors with constitutive activation of the wnt signallig pathway. J Virol

[159] Kurihara T, Brough DE, Komesdi I, Kufe DW. Selectivity of a replication-competent adenovirus for human breast carcinoma cells expressing the MUC1 antigen. J Clin In‐

[160] Wildner O, Moris JC. Therapy of peritoneal carcinomatosis from colon cancer with

[161] Chung I, Deisseroth AB. Recombinant adenoviral vector containing tumor-specific Lplastin promoter fused to cytosine deaminase gene as atranscription unit: generation

[162] Akbulut H, Zhang L, Tang Y, Deisseroth A. The cytotoxic effect of replication compe‐ tent adenoviral vectors carrying L-plastin promoter regulated E1A and cytosine de‐ aminase genes in cancers of the breast, ovary and colon. Cancer Gene Ther

[163] Akbulut H, Tang Y, Deisseroth A. Vector vaccination and vector targeted chemother‐

[164] Hashiro G, Loh PC, Jav ST. The preferential cytotoxicity of reovirus for cetain trans‐

pathway produces anti-glioma effect in vivo. Oncogene 1999;19:1–11.

systemic anti-tumoral efficacy. Nat Med 2000;6:1134–1139.

of hepatocellular carcinoma. Hum Gene Ther 1999;10:1721–1733.

oncolytic adenoviruses. J Gene Med 2000;2:353–360.

and functional test. Arch Pharm Res. 2004;27:633–639.

apy in solid tumors. J BUON 2009;14:141–146.

formed cell lines. Arch Virol 1977;75:3335–3342.

col 2002;20:1562–1569.

32 Gene Therapy - Principles and Challenges

2563.

2001;75:2857–2865.

vest 2000;106:763–771.

2003;10:388–395.


[189] Shashkova EV, Spencer JF, Wold WS, Doronin K. Targeting interferon-alpha increas‐ es antitumor efficacy and reduces hepatotoxicity of E1A-mutated spread- enhanced oncolytic adenovirus. Mol Ther 2007; 15: 598–607.

[177] Ma HI, Lin SZ, Chiang YH, Li J, Chen SL, Tsao YP, Xiao X. Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associ‐

[178] Jin RJ, Kwak C, Lee SG, Lee CH, Soo CG, Park MS, Lee E, Lee SE.. The application of an anti-angiogenic gene (thrombospondin-1] in the treatment of human prostate can‐

[179] Tanaka T, Manome Y, Wen P, Kufe DW, Fine HA. Viral vector-mediated transduc‐ tion of a modified platelet factor 4 cDNA inhibits angiogenesis and tumor growth.

[180] Maemondo M, Narumi K, Saijo Y, Usui K, Tahara M, Tazawa R, K, Matsumoto K, Nakamura T, Nukiwa T. Targeting angiogenesis and HGF function using an adeno‐ viral vector expressing the HGF antagonist NK4 for cancer therapy. Mol Ther

[181] Griscelli F, Li H, Cheong C, Opolon P, Bennaceur-Griscelli A, Vassal G, Soria J, Soria C, Lu H, Perricaudet M, Yeh P. Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model. Proc Natl Acad Sci U S A 2000; 97:6698–6703.

[182] Varda-Bloom N, Shaish A, Gonen A, Levanon K, Greenbereger S, Ferber S, Levkovitz H, Castel D, Goldberg I, Afek A, Kopolovitc Y, Harats D. Tissue specific gene thera‐

[183] Kaliberov SA, Buchsbaum DJ, Gillespie GY, Curiel DT, Arafat WO, Carpenter M, Stackhouse MA. Adenovirus-mediated transfer of BAX driven by the vascular endo‐ thelial growth factor promoter induces apoptosis in lung cancer cells. Mol Ther

[184] Savontaus MJ, Sauter BV, Huang TG, Woo SL. Transcriptional targeting of condition‐ ally replicating adenovirus to dividing endothelial cells. Gene Ther 2002;9:972–979.

[185] Nör JE, Hu Y, Song W, Spencer DM, Núñez G. Ablation of microvessels in vivo upon

[186] Nguyen JT, Wu P, Clouse ME, Hlatky L, Terwilliger EF. Adeno-associated virusmediated delivery of antiangiogenic factors as an antitumor strategy. Cancer Res

[187] Li H, Lu H, Griscelli F, Opolon P, Sun LQ, Ragot T, Y, Belin D, Soria J, Soria C, Perri‐ caudet M, Yeh P. Adenovirus-mediated delivery of a uPA/uPAR antagonist sup‐ presses angiogenesis dependent tumor growth and dissemination in mice. Gene Ther

[188] Dranoff G. GM-CSF-based cancer vaccines. Immunol Rev 2002; 188: 147–154.

py directed to tumor angiogenesis. Gene Ther 2001;8:819–827.

dimerization of Caspase-9. Gene Ther 2002; 9:444–451.

ated viral (AAV) vector. Gene Ther 2002; 9:2–11.

cer xenografts. Cancer Gene Ther 2000;7:1537–1542.

Nat Med 1997;3:437–442.

2002;5:177–185.

34 Gene Therapy - Principles and Challenges

2002;6:190–198.

1998;58:5673–5677.

1998;5:1105–1113.

