Wild-type adenovirus decreases tumor xenograft growth, but despite viral persistence complete tumor responses are rarely achieved - Deletion of the viral E1b-19-kD gene increases the viral oncolytic effect

Strategies to target viral replication to tumor cells hold great promise fo r the treatment of cancer, but even with replicating adenoviruses complete tumor responses are rarely achieved. To evaluate replicating adenoviral vec tors, we have used A549 human lung cancer nude mouse xenografts as a model system. Intratumoral injection of wild-type adenovirus (Ad309) significantl y reduced tumor growth from day 14 (p = 0.04) onward; however, tumor volume s reached a plateau at day 50. At 100 days, high levels of titratable virus were present within persistent viable tumors. In contrast to viral injecti on into established tumors, when tumor cells were infected in vitro with wi ld-type virus and then mixed with uninfected tumor cells, 1% of infected ce lls was sufficient to prevent tumor establishment. An E1b-19kD-deleted vira l mutant (Ad337) was more efficient than Ad309 in this cell-mixing model. J ust 1 cell in 1000 infected with Ad337 prevented tumor growth. However, alt hough better than wild-type virus, Ad337 was unable to eradicate establishe d flank tumors. These data suggest that although replicating adenoviruses e xhibit significant oncolytic activity, barriers within the established tumo r, such as connective tissue and tumor matrix, may limit the spread of viru s. Strategies to enhance viral spread through established tumors are theref ore likely to greatly improve the therapeutic efficacy of replicating adeno viruses.