Second-generation replication-competent oncolytic adenovirus armed with improved suicide genes and ADP gene demonstrates greater efficacy without increased toxicity.
Replication-competent adenovirus-mediated suicide gene therapy has proven to be safe in humans when delivered intraprostatically. Although signs of efficacy are emerging, it is likely that further improvements will be needed before this technology will have widespread applicability in the clinic. Toward this end, we have developed a second-generation, replication-competent adenovirus (Ad5-yCD/mutTK(SR39)rep-ADP) containing an improved yeast cytosine deaminase (yCD)/mutant(SR39) herpes simplex virus thymidine kinase fusion (yCD/mutTK(SR39)) gene and the adenovirus death protein (ADP) gene. Relative to the first-generation Ad5-CD/TKrep adenovirus, Ad5-yCD/mutTK(SR39)rep-ADP demonstrated greater tumor cell kill in vitro and significantly greater tumor control in preclinical models of human cancer. Quantification of transgene volume following direct injection of fadenovirus into human tumor xenografts and the naïve canine prostate demonstrated that ADP enhanced adenoviral spread in vivo. Toxicology studies were performed to determine whether the improved yCD/mutTK(SR39) fusion and ADP genes increased toxicity. Intraprostatic injection of Ad5-yCD/mutTK(SR39)rep-ADP did not result in significantly increased toxicity relative to the parental Ad5-CD/TKrep adenovirus, the latter of which has proven to be safe in two Phase I prostate cancer clinical trials. Together, these results provide the scientific basis for evaluating the safety and efficacy of the second-generation Ad5-yCD/mutTK(SR39)rep-ADP adenovirus in humans.
Barton
Kenneth N
KN
Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202, USA.
Paielli
Dell
D
Zhang
Yingshu
Y
Koul
Sweaty
S
Brown
Stephen L
SL
Lu
Mei
M
Seely
John
J
Kim
Jae Ho
JH
Freytag
Svend O
SO
D017503:Adenovirus E3 Proteins / Q000008:administration & dosage / Q000235:genetics* / Q000502:physiology; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004285:Dogs; D041722:Genes, Transgenic, Suicide / Q000502:physiology*; D005822:Genetic Vectors / Q000235:genetics / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D014779:Virus Replication / Q000235:genetics*
D017503:Adenovirus E3 Proteins; C099609:adenovirus death protein, Adenovirus