Evaluation of Twenty Human Adenoviral Types and One Infectivity-Enhanced Adenovirus for the Therapy of Soft Tissue Sarcoma

Abstract

The clinical course of sarcoma warrants the development of new therapeutic options, such as gene therapy. However, the lack of coxsackievirus-adenovirus receptor (CAR) on sarcoma cells limits the efficacy of adenovirus type 5 (Ad5)-based gene therapy. In this study we evaluated 20 different adenoviral types and 1 Ad5 vector with RGD-containing fiber for their internalization efficiency in sarcoma cells. We demonstrated that adenovirus types 35, 3, 7, 11, 9, and 22 and Ad5lucRGD virions (ranked in descending order) have significantly higher internalization efficiency in the tested sarcoma cells when compared with Ad5. On the basis of these results we developed a conditionally replication-competent adenoviral vector, Ad5Delta24.Ki.COX, and compared its oncolytic efficacy with that of Ad5/35Delta24.Ki.COX, an Ad5-based vector with the Ad35 fiber shaft and knob domains. Because both vectors differed only in the fiber, we were able to assess whether the adenoviral type with the most efficient internalization resulted also in enhanced treatment efficacy. We evaluated the antineoplastic activity of the oncolytic adenoviral vectors alone or in combination with the expression of measles virus fusogenic membrane glycoproteins and/or ifosfamide. The findings of our xenograft model were as follows: animals that received Ad5/35-based therapy had significantly smaller tumors than animals treated with the homologous Ad5-based vectors. In addition, we demonstrated that the combination of virotherapy, intratumoral expression of fusogenic membrane glycoproteins, and ifosfamide was clearly superior compared with treatment with individual components alone or as combinations of two components. In conclusion, Ad35-based vectors are promising for the treatment of sarcoma.