Oncolytic adenoviruses are promising anticancer agents due to their ability to self-amplify at the tumor mass. However, tumor stroma imposes barriers difficult to overcome by these agents. Transgene expression is a valuable strategy to counteract these limitations and to enhance antitumor activity. For this purpose, the genetic backbone in which the transgene is inserted should be optimized to render transgene expression compatible with the adenovirus replication cycle and to keep genome size within the encapsidation size limit. In order to design a potent and selective oncolytic adenovirus that keeps intact all the viral functions with minimal increase in genome size, we inserted palindromic E2F-binding sites into the endogenous E1A promoter. The insertion of these sites controlling E1A-Δ24 results in a low systemic toxicity profile in mice. Importantly, the E2F-binding sites also increased the cytotoxicity and the systemic antitumor activity relative to wild-type adenovirus in all cancer models tested. The low toxicity and the increased potency results in improved antitumor efficacy after systemic injection and increased survival of mice carrying tumors. Furthermore, the constrained genome size of this backbone allows an efficient and potent expression of transgenes, indicating that this virus holds promise for overcoming the limitations of oncolytic adenoviral therapy.
Bibliographical noteFunding Information:
We thank Blanca Luena, Cristina Puig, Eduard Serra, and Liz Hodgkins for their technical assistance. J.J.R. and S.G. were supported by a predoctoral fellowship (FI) granted by the Generalitat de Catalunya. This work was supported by BIO2008-04692-C03-01 (R.A.) and FIS grant PI08/1661 (M.C.) from the Ministerio de Ciencia y Tecnología of the Government of Spain, by 2005-SGR-00727 from the Departament d’Universitats, Recerca i Societat de la Informació of the Generalitat de Catalunya (R.A.), by grant C1007/A6688 from Cancer Research UK (P.F.S.) and by the Birmingham Experimental Cancer Medicine Centre (award C1520, P.F.S.). R.A. belongs to the Network of Cooperative Research on Cancer (C03-10), Instituto de Salud Carlos III of the Ministerio de Sanidad y Consumo, Government of Spain. The authors declared no conflict of interest.