Combined adenovirus-mediated nitroreductase gene delivery and CB1954 treatment: A well-tolerated therapy for established solid tumors

Gene-directed enzyme prodrug therapy (GDEPT) is a refinement of cancer chem otherapy that generates a potent cell-killing drug specifically in tumor ce lls by enzymatic activation of an inert prodrug. We describe in vivo studie s that evaluate the efficacy and safety of intratumoral (i.t.) injection of an adenovirus vector (CTL102) expressing Escherichia coli nitroreductase ( NTR) combined with systemic prodrug (CB1954) treatment. A single i.t. injec tion of CTL102 (7.5 x 10(9) to -2 x 10(10) particles) followed by CB1954 tr eatment produced clear anti-tumor effects in subcutaneous (s.c.) xenograft models of four cancers that are likely candidates for GDEPT (i.e., primary liver, head and neck, colorectal and prostate). Virus dose-response studies (s.c. liver model) revealed a steep increase and subsequent rapid plateaui ng of both NTR gene delivery and antitumor efficacy. Evidence of minor viru s spread (toxicity) was observed in a s.c. head and neck xenograft model. T his was eliminated by passive immunization with neutralizing anti-Ad5 antib odies prior to virus injection without reducing the magnitude of the anti-t umor effect. Preexisting anti-Ad5 neutralizing antibodies may therefore be an advantage rather than an issue in the clinical use of this new therapy.