Effect of preexisting immunity on oncolytic adenovirus vector INGN 007 antitumor efficacy in immunocompetent and immunosuppressed Syrian hamsters.
Immune responses against adenovirus (Ad) vectors pose a possible concern for the outcome of treatment efficacy. To address the role of preexisting immunity in oncolytic Ad vector antitumor efficacy following intratumoral injection of vector as well as tumor-to-tissue spread of the vector, we employed the Syrian hamster model. These animals are immunocompetent, and their tumors and tissues are permissive for replication of Ad type 5 (Ad5). We used the adenovirus death protein-overexpressing Ad5-based vector INGN 007. Subcutaneous tumors were established in groups of hamsters that were or were not immunized with Ad5. Half of the hamsters in these groups were immunosuppressed with cyclophosphamide. For all groups, tumors injected with INGN 007 grew significantly more slowly than those injected with buffer. Under immunocompetent conditions, there was no significant effect of preexisting immunity on vector antitumor efficacy. Soon after the tumors in naïve animals were injected with vector, the hamsters developed neutralizing antibody (NAb) and the difference in NAb titers between the naïve and immunized groups diminished. Under immunosuppressed conditions, preexisting NAb did significantly reduce vector efficacy. Thus, NAb do reduce vector efficacy to some extent, but immunosuppression is required to observe the effect. Regarding vector toxicity, there was spillover of vector from the tumor to the liver and lungs in naïve immunocompetent hamsters, and this was nearly eliminated in the immunized hamsters. Thus, preexisting immunity to Ad5 does not affect INGN 007 antitumor efficacy following intratumoral injection, but immunity prevents vector spillover from the tumor to the liver and lungs.
Dhar
Debanjan
D
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, 1100 S. Grand Blvd., Saint Louis, Missouri 63104, USA.
Spencer
Jacqueline F
JF
Toth
Karoly
K
Wold
William S M
WS
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003520:Cyclophosphamide / Q000494:pharmacology; D005822:Genetic Vectors / Q000627:therapeutic use*; D006801:Humans; D007121:Immunocompetence; D007165:Immunosuppression Therapy; D008099:Liver / Q000821:virology; D008168:Lung / Q000821:virology; D008647:Mesocricetus; D023421:Models, Animal; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000276:immunology*; D014779:Virus Replication
D000914:Antibodies, Viral; D003520:Cyclophosphamide