Oncolytic adenoviridae are human adenoviruses that have been genetically manipulated in such a way as to allow for replication in tumor cells to destroy the tumor.
Adenoviridae, which are non-enveloped double-stranded DNA viruses, can cause pharyngitis, upper respiratory infection, and conjunctivitis, depending upon serotype. Adenoviruses are cytotoxic to human cells, which results in the cell bursting and spreading to other target cells. This feature makes them potentially very useful in oncology therapy.
Wild type adenoviruses can be modified to enhance tumor replication properties. The most common modification is deletion of the viral genes that are interactive with the tumor suppressor genes; inclusion in the genome of the virus transcription elements sensitive to upregulated transcription factors in cancer cells; and tropism modification to infect cancer cells more potently.
Oncolytic Adenovirus For Cancer Treatment
Since metastatic and recurrent cancer is largely incurable, advances in oncolytic adenovirus therapy are of great importance. Oncolytic adenoviruses have been safely used in clinical settings, yet their efficacy is not sufficient at this time to eradicate most tumors. Clinical application is currently restricted to local application, and only when combating primary tumors. Poor tumor-cell targeting and immunological obstacles stand in the way of wider use. Therapies that employ oncolytic adenoviruses that will eliminate primary and metastatic cancers are needed for real alternative viable approaches.
Design of oncolytic adenoviruses (ADs) that express immune stimulating genes is now being employed. These immunotherapeutics exert systemic anti-tumor immunity and eradicate both primary and metastatic cancers even when restricted to local viral delivery. Furthermore, this therapy in concert with dendritic cell-based vaccine or radiotherapy strengthens the systemic tumor specific immunity and can result in suppression of both local and distant metastatic growth.
In past decades, notably during the 1990’s, effort was made to overcome the less than optimal delivery of therapeutic genes to cancer cells. Retroviral vectors were sustituted for adenoviral vectors, but it was concluded that even with this substitution adenoviral vectors were not capable of transducing enough tumor cells to achieve a significant therapeutic benefit. The next phase was to overcome the “delivery problem” by the use of tumor selective oncolytic adenovirus. These adenoviruses differed from the AD vectors in that they could replicate. Replication meant that the adenovirus within the tumor should be able to multiply and cause progressive spread of the virus, potentially targeting every cancer cell in that tumor.
Success of this approach is based on the capability of delivering replication competent viral genome to targeted cells with a high level of efficiency. Using the adenovirus vector paradigm, there are three strategies that are useful in retargeting. The first employs heterologous retargeting ligands that bind to the viral vector and also to a cell surface objective area. The second method makes use of viral vectors that are genetically modified and in which contain a cellular retargeting ligand. A third method involves construction of chimeric recombinant vectors, and then requires the exchange of a capsid protein from one virus to another. These retargeting endeavors can possibly reduce harmful side effects, and multiply the index of viral agents to a therapeutic load.
China has already patented an oncolytic adenovirus therapy for use in head and neck cancers. Clinical trials are ongoing to ascertain the efficacy of other oncolytic adenovirus therapies for other forms of cancer. Under the right circumstances, adenoviruses have shown the capability of not only targeting, but destroying cancer cells in humans.
The Future Of Oncolytic Adenovirus Therapy
Oncolytic adenovirus therapy is a rapidly growing field which is almost certainly destined to be part of the future of cancer therapy. The past barriers and obstacles in this therapy are being overcome every day as new knowledge is acquired. A wide variety of viruses are now being manipulated and tested in various forms of cancers, and this is ongoing with the advent of biotechnology and genetic engineering. Clinical trials worldwide are seeing good results and high success rates using oncolytic adenoviruses. More clinical trials are progressing with new viral vectors for treatment of even the intractable cancers. Active research is progressing that improves accessibility and safety of oncolytic adenovirus therapy. Advances in large-scale genome modification tools as well as advances in knowledge in molecular biology are making it possible for the new oncolytic vectors to incorporate engineered non-viral intracellular parasites, hybrid synthetic vectors, or still undiscovered gene delivery systems to aid in this ongoing march to find and employ safer and more targeted treatments. The current research and trials in the field of oncolytic adenoviruses is ushering in a new era in treatment of patients with heretofore untreatable cancers.
image provided by Xavier Bofill-De Ros (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons