Clinical Trials With Modified Adenoviruses

No trials have yet been completed with targeted adenoviruses. Nevertheless, numerous trials are in progress. Specifically, an ovarian cancer trial using the Fab-FGF2 adapter for targeting an Ad coding for HSV-TK (and subsequent ganciclovir administration) to FGF receptors is in progress (Hemminki, personal communication). Modification of the fiber with RGD-4C has been used to create advanced generation vectors for human trials. RGDTKSSTR incorporates an HSV-TK cassette for cell killing and ganciclovir analog imaging, whereas the somatostatin receptor cassette can be used for somatostatin analog imaging. The agent achieved effective killing of ovarian cancer substrates including cell lines, primary tumor samples, and efficacy in murine models of human ovarian cancer (58,59). Also, noninvasive imaging was performed and found feasible even during ganciclovir treatment for a period of more than 2 weeks (58).

RGDTKSSTR was used to demonstrate an important aspect of fiber modified Ads. Neutralizing antibodies (NAbs) are the main component of the humoral immune system responsible for inhibition of Ad infection, and are present in a large proportion of the population. Further, NAb titers are quickly induced following treatment with Ad (127). Many NAbs are conformation sensitive, and when the fiber shape is changed slightly, such as when incorporating a targeting moiety, partial escape from NAbs can be seen

(58,59,127,128). An ovarian cancer trial with RGDTKSSTR is in process (Hemminki, personal communication). A similar virus employing a cytosine deaminase prodrug-converting enzyme has been tested for treatment of head and neck cancer and a trial is pending (Hemminki, personal communication). The first transductionally targeted CRAd trial with Ad5-A24RGD has received National Cancer Institute funding and will soon start enrolling glioma and ovarian cancer patients (Hemminki, personal communication).

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