Current Developments In Adenovirus-Based Cancer Gene Therapy

Rein, Daniel T.; Breidenbach, Martina; Curiel, David T.

doi:10.2217/14796694.2.1.137

Cited by 102 publications

(92 citation statements)

References 55 publications

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“…[1][2][3] For this purpose, the variety of oncolytic viruses such as adenovirus, herpes simplex virus, influenza virus, Newcastle disease virus, poliovirus, reovirus, vaccinia virus and vesicular virus have been developed. 1,3 In the context of conditionally replicative adenoviruses (CRAds), two strategies have been employed to restrict virus replication to target cells.…”

Section: Introductionmentioning

confidence: 99%

“…An alternative strategy is to construct viruses in which the transcription of E1 genes is restricted to tumor cells by either a tumor or a tissuespecific promoter. 2,3 However, a leak of an oncolytic adenovirus from the virus-replicating tumors into systemic circulation often causes ectopic transduction of vital organs such as the liver. 2 Therefore, the suppression of naive viral tropism is needed to reduce the undesirable infection of nontarget normal tissues.…”

Section: Introductionmentioning

confidence: 99%

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Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Nishimoto

Yoshida²,

Miura³

et al. 2009

Gene Ther

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A conditionally replicative adenovirus is a novel anticancer agent designed to replicate selectively in tumor cells. However, a leak of the virus into systemic circulation from the tumors often causes ectopic infection of various organs. Therefore, suppression of naive viral tropism and addition of tumor-targeting potential are necessary to secure patient safety and increase the therapeutic effect of an oncolytic adenovirus in the clinical setting. We have recently developed a direct selection method of targeted vector from a random peptide library displayed on an adenoviral fiber knob to overcome the limitation that many cell type-specific ligands for targeted adenovirus vectors are not known. Here we examined whether the addition of a tumor-targeting ligand to a replication-competent adenovirus ablated for naive tropism enhances its therapeutic index. First, a peptide-display adenovirus library was screened on a pancreatic cancer cell line (AsPC-1), and particular peptide sequences were selected. The replication-competent adenovirus displaying the selected ligand (AdDCAR-SYE) showed higher oncolytic potency in several other pancreatic caner cell lines as well as AsPC-1 compared with the untargeted adenovirus (AdDCAR). An intratumoral injection of AdDCAR-SYE significantly suppressed the growth of AsPC-1 subcutaneous tumors, and an analysis of adenovirus titer in the tumors revealed an effective replication of the virus in the tumors. Ectopic liver gene transduction following the intratumoral injection of AdDCAR-SYE was not increased compared with the AdDCAR. The results showed that a tumor-targeting strategy using an adenovirus library is promising for optimizing the safety and efficacy of oncolytic adenovirus therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Nishimoto

Yoshida²,

Miura³

et al. 2009

Gene Ther

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“…A compelling target may be ovarian cancer, shown to overexpress these receptors, 86 and to form tumors in the peritoneal cavity. 87,88 In addition, mouse tumor models for ovarian cancer are available and have been used previously to assess Ad vectors 89,90 One reason for previous failure of Ad trials in ovarian tumors is low or variable CAR levels, 88,89,91 which the retargeted virus may be able to overcome.…”

Section: Discussionmentioning

confidence: 99%

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

et al. 2012

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Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-a (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads.Cancer Gene Therapy (2012) 2,3 In addition to being among the most extensively studied viral vectors, Ads can be easily and economically manipulated, maintained and propagated to produce high titer stocks. 4,5 Moreover, they have the capacity to carry relatively large fragments of exogenous DNA into a wide range of cell and tissue types. 4,5 Subgroup C Ads (exemplified by the most widely used Ad5 and Ad2) attach to and enter host cells in a two-step process. 6 The initial recognition/attachment step is mediated by interactions between the knob component of fiber protein on the Ad capsid and the extracellular domain of the coxsackieadenovirus receptor (CAR) on the host cell surface. 7-11 This attachment is followed by a second interaction between the RGD motif in the penton base of the virus capsid and a v b 3 or a v b 5 cell surface integrins (secondary Ad receptors), which allows viral entry via receptor-mediated endocytosis. [12][13][14][15] Both the primary and secondary Ad receptors are expressed on a wide range of tissues leading to the observed broad tissue tropism of Ads. 16,17 Unfortunately, a large number of tumor cells appear relatively refractory to Ad infection because of limited surface expression of the primary Ad receptor. 1,[18][19][20][21][22][23] This observation has been a driving force behind recent intensive efforts to generate Ad viral vectors with altered tropism.

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“…Adenoviruses (Ads) are widely applied in cancer gene therapy due to their advantages over other vectors, such as effective gene delivery and expression, the ability to transduce both dividing and nondividing cells, the ease of manipulation and the capability to produce high titers of current good manufacturing practice quality. 1 Traditional replication-defective Ad vectors, which are deleted in E1 or together with E3 region and usually propagated in E1-transformed 293 cells, can not replicate and express their genomes to produce progeny viruses in other cells after infection, due to the absence of viral E1 proteins.…”

Section: Introductionmentioning

confidence: 99%

“…4 Two strategies have been used to construct oncolytic Ads. 1,5 One strategy is to construct genetic complementation-type (type 1) CRADs, such as ONYX-015. These CRADs contain mutation(s) in key viral gene(s), which can be complemented in tumor cells but not in normal cells.…”

Section: Introductionmentioning

confidence: 99%

A simplified system for generating oncolytic adenovirus vector carrying one or two transgenes

Zb¹,

Wu²,

Wang³

et al. 2007

Cancer Gene Ther

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Oncolytic adenoviruses, also called conditionally replicating adenoviruses (CRADs), have been widely applied in cancer gene therapy. However, the construction of CRADs is still time-consuming. In this study, we attempted to establish a simplified method of generating CRADs based on AdEasy system. A novel plasmid pTE-TPE-GM was constructed, containing sequentially positioned promoter of telomerase reverse transcriptase (TERTp), coding sequence of E1A gene, promoter of E1B gene, granulocytemacrophage colony-stimulating factor (GM-CSF) gene, internal ribosome entry site sequence and coding sequence of E1B55K gene. The CRAD-generating system reported here include three plasmids: pTE-TPE-GM, pShuttle-CMV and AdEasy-1, one Escherichia coli strain BJ5183, and the packaging cell line 293. Using this system, an oncolytic adenovirus carrying B7-1 (CD80) and GM-CSF genes was successfully constructed and designated as Ad-CD80-TPE-GM. The expression of GM-CSF increased more than 9000 times in tumor cell lines infected by Ad-CD80-TPE-GM at a multiplicity of infection (MOI) of 5, compared with the cells infected by replication-defective control virus. Similarly, the expression of CD80 also increased 9-140 times. Ad-CD80-TPE-GM selectively replicates in TERT-positive tumor cells, and the progeny viruses can reach up to 375 infection units (IU) per cell. In vitro study showed that the Ad-CD80-TPE-GM induced an obvious oncolytic effect at MOI of 0.1, and killed about 80% TERT-positive tumor cells within 7 days at an MOI of 1. The antitumor effect of this vector was also investigated in Hep2 xenograft model of nude mice, and the tumor inhibition rate reached 74% at day 30 after the administration with a total dose of 1 Â 10 9 IU Ad-CD80-TPE-GM. Intratumoral injection of Ad-CD80-TPE-GM slightly induced neutralizing antibody against the oncolytic adenovirus in nude mice, which might contribute to the virus clearance in vivo. In conclusion, we successfully constructed an oncolytic CRAD carrying GM-CSF and CD80 gene. More importantly, this system can be modified to generate novel transcriptionally regulated CRADs with different tissue-specific promoters or transgenes.

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Current Developments In Adenovirus-Based Cancer Gene Therapy

Cited by 102 publications

References 55 publications

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

Oncolytic virus therapy for pancreatic cancer using the adenovirus library displaying random peptides on the fiber knob

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

A simplified system for generating oncolytic adenovirus vector carrying one or two transgenes

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