Combinatorial treatment with oncolytic adenovirus and helper-dependent adenovirus augments adenoviral cancer gene therapy.
Oncolytic adenoviruses (Onc.Ads) produce significant antitumor effects but as single agents they rarely eliminate tumors. Investigators have therefore incorporated sequences into these vectors that encode immunomodulatory molecules to enhance antitumor immunity. Successful implementation of this strategy requires multiple tumor immune inhibitory mechanisms to be overcome, and insertion of the corresponding multiple functional genes reduces the titer and replication of Onc.Ads, compromising their direct ant-tumor effects. By contrast, helper-dependent (HD) Ads are devoid of viral coding sequences, allowing inclusion of multiple transgenes. HDAds, however, lack replicative capacity. Since HDAds encode the adenoviral packaging signal, we hypothesized that the coadministration of Onc.Ad with HDAd would allow to be amplified and packaged during replication of Onc.Ad in transduced cancer cells. This combination could provide immunostimulation without losing oncolytic activity. We now show that coinfection of Onc.Ad with HDAd subsequently replicates HDAd vector DNA in trans in human cancer cell lines in vitro and in vivo, amplifying the transgenes the HDAd encode. This combinatorial treatment significantly suppresses the tumor growth compared to treatment with a single agent in an immunocompetent mouse model. Hence, combinatorial treatment of Onc.Ad with HDAd should overcome the inherent limitations of each agent and provide a highly immunogenic oncolytic therapy.
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
Lisa
L
Farzad
ImmunoViroTherapy Lab, Center for Drug Research and Division of Pharmaceutical Bioscience, Haartman Institute University of Helsinki , Helsinki, Finland.
Vincenzo
V
Cerullo
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatric, Baylor College of Medicine, Houston, Texas, USA.
Shigeki
S
Yagyu
Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, Texas, USA.
Terry
T
Bertin
Department of Pathology and Transplantation Laboratory, Cancer Gene Therapy Group, Haartman Institute University of Helsinki , Helsinki, Finland.
Akseli
A
Hemminki
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatric, Baylor College of Medicine, Houston, Texas, USA.
Cliona
C
Rooney
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Brendan
B
Lee
Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
Masataka
M
Suzuki