Switching the fiber knob of oncolytic adenoviruses to avoid neutralizing antibodies in human cancer patients.

BACKGROUND Oncolytic adenoviruses are an attractive strategy for treating cancers resistant to conventional treatments. However, their systemic utility could be limited as a result of the high prevalence of pre-existing immunity towards the vector. Furthermore, neutralizing antibodies (NAbs) may prevent successful intravenous readministration of the same agent. Previous preclinical reports indicate that the NAb response can be partially overcome by modifying the adenoviral fiber knob. However, to date, this strategy has not been evaluated in human patients. METHODS Twenty-four human patients with advanced cancer were treated with two cycles of oncolytic adenoviruses, featuring three capsid variants: unmodified adenovirus serotype 5 (Ad5), serotype 5 with RGD motif in the HI-loop of the fiber knob (Ad5-RGD) and serotype 5 carrying fiber knob from serotype 3 (Ad5/3). A virus with different fiber structure was used for the second round of treatment and patient serum was analyzed for a neutralizing effect. RESULTS All patients developed NAbs against the virus that they were treated with. However, the magnitude and velocity of the response varied considerably. When measured just before the second treatment cycle, a differential in serum NAb titer against the first versus second virus was seen in 83% of cases, suggesting that even minor changes in the fiber knob can circumvent neutralization in cancer patients. No correlation between NAb titers and outcome variables was observed. CONCLUSIONS The results obtained in the present study extend previous preclinical reports into human cancer patients and suggest that modification of the fiber knob is a feasible strategy for circumventing the NAb response in patients receiving multiple rounds of oncolytic adenoviruses.