Viral Oncology

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Introduction

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

By Erick Ditmars

Viral oncology is a subsection of Oncology that focuses on treating tumors with viruses and is the most recent and arguably most promising new age tool we have for treating cancer. While this field has gotten a lot of press in recent years the idea of using viruses as oncolytic agents has been around since the early 1920’s, since as early as the mid-1800’s doctors noticed that certain illnesses would cause remission in cancer patients. These patients usually had blood based cancers such as leukemia or lymphoma with significant immune suppression. The most famous report of this type was made by Dock1 in which a 47 year old woman with “Myelogenous leukemia” went into remission after a flu infection. This report was first made in 1896, a whole 37 years before influenza was proven to be caused by a virus. Another more shocking case is that of a 4 year old boy with lymphatic leukemia who contracted chickenpox. His liver and spleen and lymph nodes were all severely swollen and his leukocyte count was greatly elevated (200 cells/ul) after contracting chicken pox his liver, spleen returned to normal size and his white count fell back into normal levels (4.1 cells/ul). However, in both cases the remission was short lived and the cancer soon returned. The first attempt to use viruses in oncology was the treatment of Hodgkin’s lymphoma with hepatitis in the 1950’s. While some did achieve remission for a short time many in the study also contracted Hepatitis B. The study was discontinued. A number of similar experiments were run throughout the 50’s and 60’s with minimal success and viral oncology was largely abandoned. It was almost 50 years later when a breakthrough in viral oncology came in the form of oncolytic adenovirus H101. This virus was approved by the FDA for cancer treatments in 2005 and works by targeting p53 deficient cells (most cancers are p53 deficient). Today there are many different viral pathways that medical research is focusing on in an attempt to make viruses an essential part of the cancer fighting toolbox.
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Introduce the topic of your paper. State your health service question, and explain the biomedical issues.

Why Viruses?

For a long time after the correlation between viral infection and cancer remission was first discovered researchers wondered why cancer cells made such good hosts for viral cells. It wasn’t until we began to understand the molecular and genetic mechanism behind cancer that that relationship started to become clear. Cancer cells are the product of small scale evolution which is to say that the accumulation of point mutations and chromosomal shifts result in something called chromosomal instability have resulted in a phenotype drastically different from its ancestor. Typically in cancer cells we see a selection for growth advantages over somatic cells. These increased growth factors include immunity to density and anchorage dependence as well as repression of certain apoptosis measures and the activation of genes that would not normally be transcribed, such as telomerase. While these genetic and molecular changes result in a massive increase in fitness when compared to somatic cells, often times certain defensive mechanisms are sacrificed. For example in many cancer cells a number of genetic repair enzymes are shut off as well as proteins that defend against mutations in the genome and foreign DNA. It is these defense deficits seen in so many cancer cells that viruses exploit. Without the ability to defend against foreign DNA many cancer cells are left vulnerable to most viruses. By exploiting the innate viral sensitivity of most cancer cells scientists have been able to engineer viruses that can selectively kill cancer cells and grant immunity towards cancer cells.

Section 2

Oncolytic viruses are viruses that specifically target and kill cancer cells. This process usually relies on genetically modified viruses that are only able to replicate within cancer cells. This selection is typically accomplished through the knockout of genes that repress cellular apoptosis. These cells then kill cancer cells through the lytic cycle.

Adenovirus

Adenoviruses are a class of nonenveloped (Without a lipid bilayer) viruses with a double stranded DNA genome. Adenoviruses enter the cell through endocytosis. Once in the virus enters the cell the capsid breaks apart and ruptures the endosome releasing its DNA into the host cell and eventually attaching to histone proteins to enable transcription and translation of viral genes. For an adenovirus to successfully replicate in a host cell a number of processes must be completed in succinct order. The most important of these events being the repression genes which lead to apoptosis or programmed cell death which if active would hinder the viruses ability to replicate within the cell. The adenovirus accomplishes this through 2 major gene products; E1B-19K and E1B-55K. E1B-19K does two major things in the host cell. The first and most important function of this protein is its ability to bind and sequester BAK. BAK when activated induced apoptosis by binding to BAX and forming pores in the mitochondrial wall. Apoptogenic proteins then leech from the mitochondria ultimately releasing capase and lysing the cell. In addition, this protein works to stabilized viral and cellular DNA. E1B-55K functions on a p53 dependent pathway. P53 is known as the “Guardian of the Genome” and works to regulate the cell cycle, check for mutations in the genomes and initiate apoptosis. E1B-55K binds to p53 and adds a repression domain to the protein. This results in p53 acting as a repressor instead of an activator for the various apoptotic genes it would normally bind. Additionally this gene results in the modified p53 having a binding affinity 10 times stronger than the original p53. This effectively eliminates all p53 dependent apoptosis pathways allowing adenovirus to replicate without programmed cell death.

In 1996 Frank McCormic had an idea that an adenovirus without its E1B-55K gene could selectively target cancer cells due to their lack of an active p53 gene but still maintain virulence and viral defenses through the E1B-19K gene. McCormic developed the Onyx-15 adenovirus however it never reached Phase III and was therefore never tested on human patients. However, the Sunway group in china took McCormics research and developed the H101 strain which contained a complete E1B-55KB deletion. This strain boasted a 79% response rate when coupled with chemotherapy while chemotherapy alone only resulted in a 40% response rate. 

Herpesvirus

Herpesviridae is a class of enveloped viruses with double stranded DNA that cause latent infections that when triggered can become lytic. Herpesvirus enters the cell using viral Glycoproteins attached to the outside of its lipid bilayer that attach to the host cells cell membrane, causing the cell to internalize the herpes virion. Once the viron enters the cell it rapidly decays and viral DNA migrates to the nucleus where transcription and replication of viral genes begins to take place. Herpesvirus was one of the first classes of viruses that was successfully turned oncogenic with the HSV1716 strain, a mutant form of the herpes simplex virus 1. HSV1716 takes advantage of herpes innate defense systems target cancer cells in a mechanism relatively similar to many other oncolytic viruses like H101. HSV1716 contains a full deletion of the gene ICP34.5 which allows for neurovirulence (viral replication within nerve cells). The ICP34.5 gene functions by counteracting PKR mediated blocks on viral replication and apoptosis. PKR is typically activated by double-stranded RNA, PACT or heparin. Once activated PKR deactivates cellular transcription, halting viral replication. Under extreme viral stress PKR is able to induce apoptosis through the activation of inferon cytokines. PKR is also known to interact with p53 which is also known to be inactivated in cancer cells. A knockout of this gene would cause the virus to target tumor cells due to most cancer cells inactivation of PKR (PKR is known to activate PP2A, a tumor suppression protein). HSV1716 is currently undergoing a number of clinical trials to determine its usefulness in humans and is currently in phase II trials. Additionally it was reported by Liu that by upregulating US11, GM-CSF and downregulating ICP47 can increase rates of tumor destruction, tumor reduction and antigen presentation as well as enhancing anti-tumor immune response.

Section 3

Include some current research, with at least one figure showing data.

References

[1] Hodgkin, J. and Partridge, F.A. "Caenorhabditis elegans meets microsporidia: the nematode killers from Paris." 2008. PLoS Biology 6:2634-2637.

Authored for BIOL 291.00 Health Service and Biomedical Analysis, taught by Joan Slonczewski, 2016, Kenyon College.