Preclinical safety and biodistribution of adenovirus-based cancer vaccines after intradermal delivery.
The recombinant adenoviral (Ad) vector is being considered as a cancer vaccine platform because it efficiently induces immune responses to tumor antigens by intradermal immunization. The aims of this study were to evaluate the potential toxicities and biodistribution after a single dose or six weekly intradermal doses of Ad2/gp100v2 and Ad2/MART-1v2, which encode tumor-associated antigens gp100 and MelanA/MART-1, respectively. The only dose-related toxicities associated with intradermal administration of these Ad vectors were inflammatory cell infiltrates in the draining lymph nodes and injection sites that persisted 83 days after administration. The biodistribution of Ad DNA as detected by real-time polymerase chain reaction was largely confined to the injection sites and draining lymph nodes of mice treated with either a single dose or multiple doses of Ad vector and in the spleens of mice treated with multiple doses of Ad vector. Adenoviral DNA was transiently detected in the bone marrow, lung, or blood of only one animal for each site and was below the limit of assay quantification (<10 copies/microg DNA). The vector persisted in the skin and lymph nodes as long as 92 days after the last dose. We conclude that Ad vectors delivered by intradermal administration provide a safe, genetic vaccine delivery platform that induces desirable immune responses at the immunization sites and the lymph nodes that, ultimately, result in immune responses specific to the tumor antigens.
Plog
Malinda S
MS
Genzyme Corporation, Framingham, MA 01701, USA.
Guyre
Cheryl A
CA
Roberts
Bruce L
BL
Goldberg
Mark
M
St George
Judith A
JA
Perricone
Michael A
MA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D004279:DNA, Viral / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D007271:Injections, Intradermal; D058965:MART-1 Antigen; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014018:Tissue Distribution; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D004279:DNA, Viral; D058965:MART-1 Antigen; D008562:Membrane Glycoproteins; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; C548642:Pmel protein, mouse; D058951:gp100 Melanoma Antigen