Human Adenovirus Replicates in Immunocompetent Models of Pancreatic Cancer in Syrian Hamsters

Bortolanza, Sergia; Alzuguren, Pilar; Buñuales, María; Qian, Cheng; Prìeto, Jesús; Hernández-Alcoceba, Rubén

doi:10.1089/hum.2007.017

Cited by 29 publications

(40 citation statements)

References 27 publications

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“…Recently, the Syrian golden hamster has been suggested as a permissive animal for adenoviral replication. 32,33 Although this model offers the opportunity to evaluate the effect of oncolytic adenoviruses in an immunocompetent animal, hamster cells do not express fusion-competent receptors for GALV. A transgenic Pit-1 animal model permissive to human adenovirus replication would be required to test the immunogenicity of the syncytia induced by ICOVIR16.…”

Section: Discussionmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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The limitations of the current oncolytic adenoviruses for cancer therapy include insufficient potency and poor distribution of the virus throughout the tumor mass. To address these problems, we generated an oncolytic adenovirus expressing the hyperfusogenic form of the gibbon-ape leukemia virus (GALV) envelope glycoprotein under the control of the adenovirus major late promoter. The oncolytic properties of the new fusogenic adenovirus, ICOVIR16, were analyzed both in vitro and in vivo, and compared with that of its non-fusogenic counterpart, ICOVIR15. Our results indicate that GALV expression by ICOVIR16 induced extensive syncytia formation and enhanced tumor cell killing in a variety of tumor cell types. When injected intratumorally or intravenously into mice with large pre-established melanoma or pancreatic tumors, ICOVIR16 rapidly reduced tumor burden, and in some cases, resulted in complete eradication of the tumors. Importantly, GALV expression induced tumor cell fusion in vivo and enhanced the spreading of the virus throughout the tumor. Taken together, these results indicate that GALV expression can improve the antitumoral potency of an oncolytic adenovirus and suggest that ICOVIR16 is a promising candidate for clinical evaluation in patients with cancer.

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Section: Discussionmentioning

confidence: 99%

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

et al. 2011

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“…As previously reported for Ad5, human cell lines were the most efficient viral producers (up to 10 3 iu per cell), followed by HaP-T1 (10 2 iu per cell). Although progressive viral amplification has been demonstrated in the H2T cells, 21 virus yield was very low at 48 h, suggesting low permissivity and delayed viral cycle. Ad-WTLuc showed the same tendency as the parental virus, with a moderate reduction of virus production in some cell lines such as HuH-7, HaP-T1, HP-1 and H2T, and slight increase in A549 cells.…”

Section: Characterization Of the Ad-wtluc Virus In Vitromentioning

confidence: 93%

“…HaP-T1 cells or 2.5 Â 10 6 HP-1 cells following laparotomy, as previously described. 21 Viruses were injected intratumorally 2 weeks after cell implantation of HaP-T1 and HP-1 cells, and 5 weeks after implantation of H2T cells. Injection was performed in 50 ml total volume of saline solution.…”

Section: Cell Lines and Culturesmentioning

confidence: 99%

“…In this work we have constructed a vector based in the Ad5 genome, in which the firefly luciferase is inserted in the E3-6.7K/gp19K locus (Ad-WTLuc vector). Using a recently described immunocompetent model based in Syrian hamsters, 21 we have studied the persistence of replication for Ad-WTLuc versus Ad5, and the kinetics of luciferase expression of Ad-WTLuc after intratumor inoculation. Replication and spread of Ad5 and related CRAds has been previously demonstrated in Syrian hamsters.…”

Section: Introductionmentioning

confidence: 99%

“…22,23 In our specific adaptation of the model, intrahepatic injection of hamster pancreatic cancer cells gives rise to a progressive tumor growth in the liver and extensive infiltration of surrounding tissues. 21 Cells with different in vitro permissivity for adenoviral replication have been used. We describe here that immunocompetent animals eliminate Ad-WTLuc faster than Ad5 in tumors derived from the most permissive cells.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of the E3-6.7K/gp19K region reduces the persistence of wild-type adenovirus in a permissive tumor model in Syrian hamsters

et al. 2009

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A partial deletion of the adenovirus E3 region, comprising the overlapping 6.7K/gp19K genes, has been described for the incorporation of therapeutic genes in 'armed' oncolytic adenoviruses. This deletion allows the insertion of up to 2.5 kb genetic material into the virus and ensures strong expression of transgenes without reducing the replication and cytolytic potency of viruses in vitro. E3-gp19K and 6.7K proteins are involved in avoiding recognition and elimination of infected cells by the host immune system. Therefore, we have studied the effect of this deletion on the replication and transgene expression of the virus in immunocompetent models based on Syrian hamsters. Tumors were established by intrahepatic injection of pancreatic cancer cells with moderate (HaP-T1, HP-1) or low (H2T) permissivity for adenovirus replication. The wild-type human adenovirus 5 (Ad5) or a modified version containing the luciferase gene in the E3-6.7K/gp19K locus (Ad-WTLuc) were injected intratumorally. We found that elimination of Ad-WTLuc was faster than Ad5 in HaP-T1 and HP-1 tumors. In contrast, no differences were observed when the same tumor was established in severely immunocompromised NOD-scid IL2Rg null mice. In addition, virus-mediated luciferase expression was more stable in these animals. These results suggest that the lack of E3-6.7K/gp19K genes may accelerate the clearance of oncolytic adenoviruses in some immunocompetent tumor models.

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Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters

Hasegawa¹,

Abei

Yokoyama

et al. 2013

Int. J. Cancer

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Oncolytic viruses (OVs) are novel cancer therapeutics with great promise, but host antiviral immunity represents the hurdle for their efficacy. Immunosuppression by cyclophosphamide (CP) has thus been shown to enhance the oncolytic efficacy of many OVs, but its effects on OVs armed with therapeutic genes remain unknown. We have previously reported on the efficacy of AxE1CAUP, an oncolytic adenovirus (OAd) expressing uracil phosphoribosyltransferase (UPRT), an enzyme that markedly enhanced the toxicity of 5-fluorouracil (5-FU), in immunodeficient, Ad-nonpermissive nude mice. Here we explored the efficacy and safety of intratumoral (i.t.) AxE1CAUP/5-FU therapy and of its combination with CP for syngenic HaP-T1 pancreatic cancers in immunocompetent, Ad-permissive Syrian hamsters. AxE1CAUP infected, replicated, expressed UPRT, and increased the sensitivity to 5-FU in HaP-T1 cells in vitro. I.t. AxE1CAUP/5-FU treatment inhibited the growth of subcutaneous HaP-T1 allografts. The combination with high-dose CP inhibited serum Ad-neutralizing antibody formation, increased intratumoral AxE1CAUP replication and UPRT expression, and resulted in further enhanced therapeutic effects with 5-FU. Neither body weight nor histology of the liver and lung changed during these treatments. A clinically-approved, intermediate-dose CP also enhanced the efficacy of i.t. AxE1CAUP/5-FU treatment in these hamsters, which was not affected by preexisting immunity to the vector. These data demonstrate the excellent antitumor efficacy and safety of an OAd armed with a suicide gene in combination with CP for treating syngenic tumors in immunocompetent, Ad-permissive animals, indicating the efficacy of CP in overcoming the hurdle of antiviral immunity for effective OV-mediated gene therapy.

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Human Adenovirus Replicates in Immunocompetent Models of Pancreatic Cancer in Syrian Hamsters

Cited by 29 publications

References 27 publications

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

GALV expression enhances the therapeutic efficacy of an oncolytic adenovirus by inducing cell fusion and enhancing virus distribution

Deletion of the E3-6.7K/gp19K region reduces the persistence of wild-type adenovirus in a permissive tumor model in Syrian hamsters

Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters

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