Oncolytic Viruses in Cancer Treatment

by Annabelle Shilling (IV)

Vaccines have been used to prevent cancer-causing infections such as HPV, but their applications within cancer research extend further than that. While virtually every vaccine in history has been wielded to prevent the acquisition of some infectious disease, oncolytic virotherapy is a novel branch of oncology pertaining to vaccines used not to prevent an infectious disease, but designed to cure a noninfectious one. An oncolytic virus is one that seeks and destroys exclusively tumor cells. It typically does so by lysing such cells, but this direct cytoreduction is not the only effect of these viruses. A helpful byproduct of the infection is the stimulation of the immune system within the tumor microenvironment. While the viruses go about lysing tumor cells, the tumor antigens released induce both an innate and an adaptive immune response (ex. increasing tumor T-Cell counts), the latter of which functions as a lasting immunotherapy. Oncolytic viruses can be lab-made or naturally occuring; the former of which ensures the viruses must depend on tumor cells for replication and its establishment of tumor-specific alterations for lysis. The Onyx-015 Adenovirus was one of the first oncolytic viruses used in clinical trials, and in spite of its benefit proving slightly underwhelming, the trials did confirm two things: oncolytic viruses are safe to be administered to humans and they hold the potential to work in conjunction with systemic radiotherapy and chemotherapy as a combined cancer treatment. Onyx-015 is selective, not in the sense that it will not infect healthy cells, but that only healthy cells will undergo apoptosis or cell cycle arrest after becoming infected with it. With adenoviruses, quiescent cells can be pushed into S phase by E1A proteins after they bind to retinoblastoma proteins within the cell. These Rb proteins are used to regulate the transition from G1 to S phase through interactions with E2F transcription factors, and the Rb binding to E1A subsequently causes the release of E2F. E1A, undesirably, causes p14ARF to be released as well, a protein that inhibits Mdm2 (Murine double minute 2) from degrading p53. The transcription factor p53 is used to initiate cell cycle arrest or apoptosis as a consequence of signals revealing damage to DNA—it can also do this due to cellular stress. However, if p53 accumulates due to the lack of degradation, the cell cycle arrest or apoptosis that can occur is detrimental to the viral life cycle—if the cell dies or ceases growth before the viral cycle is complete,

Oncolytic virus particle by Lleyton Lance (VI)

it will reduce the amount of viral offspring produced. Adenoviruses contain E1B genes to combat this threat to their reproduction, one of which, known as E1B55K, codes a product that binds to p53 and renders it nonfunctional. Cancerous cells are those with damaged DNA that continue to replicate and exist. Thus, the lack of functional p53 is universal to almost all known cancers—the damaged DNA and resulting protein does not signal p53 to initiate apoptosis or restrict cellular growth. Onyx-015 was genetically engineered (827 bp deletion and a point mutation--causing an early stop codon-in E1B), preventing the proper expression of E1B55K’s product. Thus, in infected healthy cells, the adenovirus cannot restrict the buildup of p53. The resulting apoptosis or restricted cellular growth interferes with the viral life cycle and thus prevents the infection from spreading among healthy tissues. However, as tumor cells do not possess functional p53, the lack of functional E1B55K does not make a difference in the viral life cycle. The virus can go about replicating itself and ultimately lyse the cell without any risk of apoptosis or restricted cell growth occurring. Thus, Onyx-015 is selective in its ability to replicate in and lyse tumor cells without posing a threat to surrounding, healthy tissues. As of now, only one therapy using an oncolytic virus has been FDA-approved for cancer treatment: Talimogene laherparepvec, which is used to treat melanoma using a genetically modified herpesvirus. It bolstered the theory that oncolytic viruses can systematically target cancer manifested when tumors not directly injected with the treatment began to shrink. While none are approved by the FDA, many other viruses are being examined for oncolytic potential–even a genetically modified form of the poliovirus is now in trial for targeting brain tumors. Another treatment in development uses reoviruses capable of crossing the brainblood barrier to target brain tumors as well. While these treatments do seem very promising, there are limitations to the capabilities of oncolytic viruses. They are susceptible to neutralization, hypoxic environments, high IFPs (interstitial fluid pressures), being wiped out by the immune system, movement-inhibiting stromal barriers, and transduction errors. That being said, oncolytic viruses remain a possibility for cancer treatment, combined or solitary.

Works Cited

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