E1A-expressing adenoviral E3B mutants act synergistically with chemotherapeutics in immunocompetent tumor models.
The majority of clinical trials evaluating replication-selective oncolytic adenoviruses utilized mutants with immunomodulatory E3B genes deleted, likely contributing to the attenuated efficacy. We investigated whether an intact immune response could contribute to the observed improved efficacy in response to combinations with chemotherapeutics. Seven carcinoma cell lines were evaluated by combining viral mutants; dl309 (DeltaE3B), dl704 (DeltaE3gp19K), dl312 (DeltaE1A) or wild-type Ad5 with the commonly used clinical drugs cisplatin and paclitaxel. Synergistic effects on cell death were determined by generation of combination indexes in cultured cells. In vivo tumor growth inhibition was achieved by virotherapy alone and was most efficacious with wild-type virus and least with the DeltaE3B mutant. Significantly higher efficacy was observed when the viruses were combined with drugs. The greatest enhancement of tumor inhibition was in combination with the DeltaE3B mutant restoring potency to that of Ad5 wild-type levels, observed only in animals with intact immune response. Increases in infectivity, viral gene expression and replication were identified as potential mechanisms contributing to the synergistic effects. Our results suggest that the attenuation of DeltaE3B mutants can be overcome by low doses of chemotherapeutics only in the presence of an intact immune response indicating a role for T-cell-mediated functions.
Cheong
S C
SC
Centre for Molecular Oncology, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Wang
Y
Y
Meng
J-H
JH
Hill
R
R
Sweeney
K
K
Kirn
D
D
Lemoine
N R
NR
Halldén
G
G
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017503:Adenovirus E3 Proteins / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000819:agonists / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000819:agonists / Q000494:pharmacology*; D017353:Gene Deletion; D006801:Humans; D007111:Immunity, Cellular; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017239:Paclitaxel / Q000819:agonists / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D017503:Adenovirus E3 Proteins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D002945:Cisplatin