Rodents versus pig model for assessing the performance of serotype chimeric Ad5/3 oncolytic adenoviruses

Lisa Koodie, Matthew G. Robertson, Malavika Chandrashekar, George Ruth, Michele Dunning, Richard W Bianco, Julia Davydova

Research output: Contribution to journalArticle

Abstract

Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism.

Original languageEnglish (US)
Article number198
JournalCancers
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

Adenoviridae
Rodentia
Swine
Serogroup
Adenoviridae Infections
Mesocricetus
Cell Line
Coxsackie and Adenovirus Receptor-Like Membrane Protein
Neoplasms
Tropism

Keywords

  • Ad5/3
  • Animal model
  • Oncolytic adenovirus
  • Pig
  • Porcine
  • Preclinical model
  • Replication
  • Serotype 3
  • Species B
  • Syrian hamsters

Cite this

Rodents versus pig model for assessing the performance of serotype chimeric Ad5/3 oncolytic adenoviruses. / Koodie, Lisa; Robertson, Matthew G.; Chandrashekar, Malavika; Ruth, George; Dunning, Michele; Bianco, Richard W; Davydova, Julia.

In: Cancers, Vol. 11, No. 2, 198, 01.02.2019.

Research output: Contribution to journalArticle

Koodie, Lisa ; Robertson, Matthew G. ; Chandrashekar, Malavika ; Ruth, George ; Dunning, Michele ; Bianco, Richard W ; Davydova, Julia. / Rodents versus pig model for assessing the performance of serotype chimeric Ad5/3 oncolytic adenoviruses. In: Cancers. 2019 ; Vol. 11, No. 2.
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abstract = "Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism.",
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AB - Oncolytic adenoviruses (Ad) are promising tools for cancer therapeutics. Most Ad-based therapies utilize species C serotypes, with Adenovirus type 5 (Ad5) most commonly employed. Prior clinical trials demonstrated low efficiency of oncolytic Ad5 vectors, mainly due to the absence of Ad5 primary receptor (Coxsackie and Adenovirus Receptor, CAR) on cancer cells. Engineering serotype chimeric vectors (Ad5/3) to utilize Adenovirus type 3 (Ad3) receptors has greatly improved their oncolytic potential. Clinical translation of these infectivity-enhanced vectors has been challenging due to a lack of replication permissive animal models. In this study, we explored pigs as a model to study the performance of fiber-modified Ad5/3 chimeric vectors. As a control, the Ad5 fiber-unmodified virus was used. We analyzed binding, gene transfer, replication, and cytolytic ability of Ad5 and Ad5/3 in various non-human cell lines (murine, hamster, canine, porcine). Among all tested cell lines only porcine cells supported active binding and replication of Ad5/3. Syrian hamster cells supported Ad5 replication but showed no evidence of productive viral replication after infection with Ad5/3 vectors. Transduction and replication ability of Ad5/3 in porcine cells outperformed Ad5, a phenomenon often observed in human cancer cell lines. Replication of Ad5 and Ad5/3 was subsequently evaluated in vivo in immunocompetent pigs. Quantitative PCR analyses 7 days post infection revealed Ad5 and Ad5/3 DNA and replication-dependent luciferase activity in the swine lungs and spleen indicating active replication in these tissues. These studies demonstrated the flaws in using Syrian hamsters for testing serotype chimeric Ad5/3 vectors. This is the first report to validate the pig as a valuable model for preclinical testing of oncolytic adenoviruses utilizing Adenovirus type 3 receptors. We hope that these data will help to foster the clinical translation of oncolytic adenoviruses including those with Ad3 retargeted tropism.

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