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Identifying the safety profile of Ad5.SSTR/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in anticipation of a phase I clinical trial in patients with recurrent ovarian cancer.

AbstractPURPOSE:
The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma.
EXPERIMENTAL DESIGN:
Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthanized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects.
RESULTS:
Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribution. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggesting vector elimination over time. Animals in the Ad5.SSTR/TK.RGD +/- GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflammatory response. Toxicity in this dose cohort seemed to be reversible over time.
CONCLUSIONS:
These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.
AuthorsKellie Matthews, Patricia E Noker, Baohong Tian, Sheila D Grimes, Ronna Fulton, Karen Schweikart, Raymond Harris, Rose Aurigemma, Minghui Wang, Mack N Barnes, Gene P Siegal, Akseli Hemminki, Kurt Zinn, David T Curiel, Ronald D Alvarez
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 12 Pg. 4131-7 (Jun 15 2009) ISSN: 1557-3265 [Electronic] United States
PMID19509153 (Publication Type: Journal Article)
Chemical References
  • Receptors, Somatostatin
  • somatostatin receptor 2
  • Ganciclovir
Topics
  • Adenoviridae (genetics, metabolism)
  • Animals
  • Clinical Trials, Phase I as Topic
  • Cricetinae
  • Female
  • Ganciclovir (pharmacology)
  • Gene Transfer Techniques
  • Genetic Therapy (adverse effects)
  • Genetic Vectors (adverse effects, genetics, metabolism)
  • Mesocricetus
  • Receptors, Somatostatin (metabolism)

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