Assessment and development of adenovirus type 11 for cancer therapy

Abstract

The efficacy of oncolytic virotherapy is influenced by the interactions between the tumour, virus and host immunity. The first generation of oncolytic adenoviruses, based on serotype 5 (Ad5), has achieved limited success in clinical trials. Its shortcomings include the downregulation and inaccessibility of its receptor, the Coxsackie and adenovirus receptor (CAR) in cancer cells, high prevalence of neutralising antibodies and hepatotoxicity. In contrast, Ad11 binds to CD46 and other receptor(s) but its potential as an oncolytic virus remains to be explored. A panel of human cancer cell lines were found to express higher levels of CD46 than CAR. However, not all cell lines were more sensitive to Ad11-mediated cytotoxicity in vitro compared to Ad5. Treatment of Ad5-insensitive PC-3 human prostate cancer xenografts with Ad11 resulted in significant reduction in tumour growth, but not Ad11-insensitive MIA PaCa-2 human pancreatic cancer xenografts. Virus attachment and nuclear entry of Ad11 were significantly better than Ad5 even in cells that were insensitive to Ad11 killing. In these cells, however, Ad11 E1A mRNA levels were much lower than those of Ad5, producing a negative effect on viral DNA amplification, structural protein synthesis, progeny production and cell killing. Cells that were sensitive to Ad11 cytotoxicity showed higher levels of E1A mRNA. The region upstream of Ad5 E1A demonstrated higher transcription-enhancing activity than the corresponding region of Ad11. Two Ad11 mutants were constructed in which E1A was under the control of the Ad5 E1A promoter and enhancer-promoter, respectively. With the latter virus, improved oncolytic potency was observed. It was superior to Ad11 and also to Ad5 in many cancer cell lines, and was as effective as Ad5 in the MIA PaCa-2 xenograft model. Therefore, Ad11 with the Ad5 E1A enhancerpromoter should be used as a backbone for the future development of potent and tumour-specific oncolytic Ad11 mutants.