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.
Adenoviruses (Ads) infect a broad range of tissue types, and derived vectors have been extensively used for gene therapy. Helper-dependent Ad vectors (HDAds), devoid of viral coding sequences, allow for insertion of large or multiple transgenes in a single vector and have been preclinically used for the study of genetic disorders. However, the clinical application of Ad vectors including HDAds for genetic disorders has been hampered by an acute toxic response. This characteristic, while disadvantageous for gene replacement therapy, could be strategically advantageous for the activation of an immune response if HDAds were used as an adjunct treatment in cancer. Cancer treatments including immunotherapy are frequently limited by the inhibitory environment produced by both tumors and their stroma, each of which express numerous inhibitory molecules. Hence, multiple inhibitory mechanisms must be overcome for development of anti-tumor immunity. The large coding capacity of HDAds can accommodate multiple immune modulating transgenes that could produce a combined effect to overcome tumor-derived inhibition and ensure intratumoral effector T-cell proliferation and function. In this review, we discuss the potential advantages of HDAds to cancer immunotherapy based on potent host immune responses to Ads.
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