THE "'GOOD" VIRUS

By ANNA ARGULIAN SWATHI BALAJI

With the onset of the 2020 COVID-19 pandemic, viral research has reached a historical peak. With every university dedicated to unraveling the mechanism behind coronavirus, and every ear attuned to the latest news, the world finally awakened to a long-forgotten and slumbering pathogen: the virus. Although many had forgotten about the versatility of viruses before the pandemic, behind the scenes research rapidly accelerated as modern technology began to cast viruses as vehicles of cancer remedy. Thus, the 21st century saw the rise of the very first “good” virus.

Since the early nineteenth century and the advent of cancer treatment, case studies have uncovered the surprising effects of infection in cancer patients. Early reports have shown how coinciding viral infections had the potential to elicit temporary tumor regression and brief remission. A modern example can be seen in a recent Clinical Cancer Research publication, where a strain of the common cold was able to induce regression in bladder cancer. With this peculiar correlation, research into virology took a sharp turn in the 1950s but simmered down around the 70s and 80s due to the limiting nature of the approach. At the time, researchers knew too little about the mechanism of tumor shrinkage as well as the possible ways to correctly harness virology to combat cancer. However, with the recent advent of gene editing and further studies into the molecular pathways involved in carcinogenesis, a new revolution in viral immunotherapy began.

A cancer prognosis is typically dependent on the present tumor microenvironment (TME). The TME can be classified into a “cold” and “hot” phenotype, where “cold” tumors are immune deserts, with minimal immune cell infiltration, and “hot” tumors are recognized by the immune system. Subsequently, the largest challenge of current immono-oncology is either turning a “cold” tumor into an immunologically responsive tumor or activating already present tumor immune cells that have been previously inhibited by various cancer mechanisms.

Thus, the attractiveness of viruses as clinical targets lies in their ability to elicit strong immune responses and bring in cytotoxic T cells to kill the infected tumor cells. Current research has targeted viral entry pathways specific to tumor cells in an effort to localize the therapy and ensure a minimized systemic effect. Furthermore, a majority of oncolytic viruses are genetically engineered to have deletions in their genome to reduce pathogenicity and instead insert various sequences that either increase specificity to the tumor or even function to produce chemotherapeutic toxins within the tumor. The year 2015 saw the very first FDA approved oncolytic virus, Talimogene Laherperepvec (T-VEC), developed by Amgen with the help of physician Igor Puzanov. Injected intratumorally, T-VEV is a modified form of the herpes virus, with two genes specifically removed that function to strengthen the virus against host immunity. The modified and

weakened form of the herpes virus is able to enter the tumor cell, alert the immune system, and break the cell down, without spreading or inducing other adverse effects. T-VEC also possesses a newly added gene coding for GM-CSF, which enhances immune system activation. T-VEC is prescribed to late stage melanoma patients and has an over 30% response rate, where 30% of patients see either tumor reduction or undergo full remission.

Another novel oncolytic virus currently undergoing multiple clinical trials is TG6002, an altered Vaccinia virus, which functions as not only an alert system for the host’s immune system, but also as a vehicle of drug delivery to the tumor site. Coded to express the precursor FCU1 gene in infected tumor cells, an orally administered pro-drug 5-FC matures into 5-FU within the tumor cells. 5-FU is a strong chemotherapeutic agent that although induces positive therapeutic results at the site of the tumor, also induces negative systemic side effects. By only activating the drug in the localized tumor area, the oncolytic virus functions both to kill tumor cells and deliver an effective synergistic agent: the chemotherapy drug. The mechanism behind the functionality of viruses in the tumor microenvironment is largely unknown. However, hundreds of clinical and bench trials are currently in progress in an attempt to elucidate the molecular pathways affected by viral attack as well as methods of genetically engineering viruses to induce greater tumor specificity and immunological response.

In a time where the word “virus” elicits fear and apprehension, it’s important to highlight oncolytic viruses in an effort to remind society how far modern medicine and research has come. Even though the current times are uncertain, it is reassuring to know that not only has society conquered this enemy before, but it has usurped it to fight its battles. We are the virus of the viruses. Soon enough, even coronavirus will do our bidding.

“First Patient Dosed With Transgene's Oncolytic

Virus TG6002, Administered by Intrahepatic

Artery Infusion in Colorectal Cancer With

Liver Metastases.” BioSpace, www.biospace. com/article/releases/first-patient-dosedwith-transgene-s-oncolytic-virus-tg6002- administered-by-intrahepatic-artery-infusionin-colorectal-cancer-with-liver-metastases/. Kaufman, Howard L., et al. “Oncolytic Viruses: a

New Class of Immunotherapy Drugs.” Nature

News, Nature Publishing Group, 1 Sept. 2015, www.nature.com/articles/nrd4663. Kelly, Elizabeth, and Stephen J Russell. “History of Oncolytic Viruses: Genesis to Genetic

Engineering.” Molecular Therapy, Cell Press, 14 Dec. 2016, www.sciencedirect.com/science/ article/pii/S1525001616313314. Lawler, Sean E. “Oncolytic Viruses in Cancer

Treatment.” JAMA Oncology, American

Medical Association, 1 June 2017, jamanetwork.com/journals/jamaoncology/ article-abstract/2536204. Mansfield, David, et al. “Viral Targeting of

Non-Muscle Invasive Bladder Cancer and Priming of Anti-Tumour Immunity

Following Intravesical Coxsackievirus

A21.” Clinical Cancer Research, American

Association for Cancer Research, 1 Jan. 2019, clincancerres.aacrjournals.org/content/ early/2019/06/29/1078-0432.CCR-18-4022.