NK cells mediate the anti-tumor effects of E1-deleted, type 5 adenovirus in a human tumor xenograft model.
SCH58500 (ACN53) is a recombinant adenovirus expressing human p53 for gene therapy of cancer. In preclinical studies, SCH58500 has shown efficacy against many tumor-types with non-functional p53. This activity arises from both p53-mediated and adenovirus vector-mediated mechanisms. The importance of NK cells for adenovirus-mediated tumor suppression after intratumoral dosing was demonstrated using MDA-MB-231 human breast cancer xenografts in scid (defective T and B cell response) and scid-beige (defective T, B, and NK cell response) mice. There was no adenovirus vector-mediated anti-tumor activity in scid-beige mice. Dexamethasone (Dex) is a potent suppressor of the cellular immune response to recombinant adenovirus in mice and rats. Dex abolished growth suppression caused by adenovirus vector, but did not interfere with the anti-tumor efficacy of p53. Supression of NK cell activity in scid mice using intravenous administration of a neutralizing antibody had the same effect as Dex. These data support a role for NK cells in adenovirus vector-mediated anti-tumor efficacy.
Nielsen
L L
LL
Tumor Biology, Schering-Plough Research Institute, Kenilworth, NJ 07033-1300, USA.
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D016158:Genes, p53; D015316:Genetic Therapy; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous
D003907:Dexamethasone