Genetically Engineered Viruses Combat Invasive Cancer

by Caroline Wechsler

58-year-old Georgia resident Nancy Justice was diagnosed with glioblastoma, a tumor of the brain, back in 2012. Though her doctors immediately combated the cancer with surgery, radiation, and chemotherapy, the tumor relapsed in late 2014, stronger than ever. According to her doctors, Justice had only seven months to live because the tumor would double in size every two weeks.¹

Invasive cancers are now one of the leading causes of death in America. The American Cancer Society reports in 2015 that there were over 1.65 million new cases of cancer, with just over 589,000 deaths per year.² So it is unsurprising that now over $130 billion is spent on researching new treatments for cancer.³ Particularly frustrating though are tumors that resurface even after being “cured,” like that of Nancy Justice. But a new, cutting edge treatment is giving people hope: using viruses, something normally thought to be harmful, as a cancer combatant.

Nancy Justice was the 17th patient entered into a revolutionary study at Duke University Medical Center using a genetically modified version of the polio virus to combat glioblastoma. After several months of treatment, her tumor has—seemingly miraculously—begun to shrink away. This project has been a work in progress for almost three decades. It is the brainchild of Matthias Gromeier, a molecular biologist who has been working on viral treatments for cancer for the last 25 years. He described the difficulty of proposing this idea, originally unthinkable. “Most people just thought it was too dangerous,” he remembers in an interview with CBS.¹ For the past 15 years, Gromeier has been at Duke, working with Dr. Henry Friedman, deputy director of the Tisch Brain Tumor Center at Duke, the other half of the duo that pushed this project through to completion. Though he too was originally skeptical about the project, Dr. Friedman now calls the polio treatment “the most promising therapy I’ve seen in my career, period.”¹

MAKING AN INVADER INTO A DEFENDER

The treatment takes advantage of viruses’ infection mechanisms. Normally, viruses infect cells by piercing their outer membranes and injecting viral DNA into the cell.⁴ The viral genetic material then hijacks the host cell’s replicating machinery, forcing it to produce viral genomes and capsids, ultimately assembling the parts into many copies of the virus that eventually burst out of the cell in a process called lysis, killing the cell.⁵ If researchers can take control of this process, they are able to attack and lyse certain cells, such as those in a tumor. The polio virus is particularly effective for this purpose because it specifically attaches to surface receptors on cells that make up most types of solid tumors.¹

In order to achieve control of the viral mechanism, the researchers used a technique called recombination—essentially, taking desired parts of viral genomes and fusing them together to create new virus DNA sequence. This technique of DNA recombination is used in many different fields. To create recombinant versions of genetic material, the desired genetic material is isolated using restriction enzymes, and then reinserted into the desired vector (in this case the polio virus) with DNA ligase, an enzyme that links strands of DNA together.⁶ The team at Duke removed a key genetic sequence from the polio which makes the virus deadly, and instead patched it up with a piece of genetic material from a relatively harmless cold virus to create the recombinant form, called PVS-RIPO.¹ Not only is PVS-RIPO effective at killing cancerous cells, but also, because of this recombination, it is incapable of reproducing in normal cells, which makes it safe to use in humans.⁷

STARTING THE BODY’S DEFENSES

Once the virus has been engineered to attack the cancer, the problem then becomes getting it to the site of the cancer. This process must be neatly tailored because the virus can still cause swelling in the area it is inserted. To do this, the Chief of Neurosurgery at Duke, Dr. John Sampson, uses 3-D MRI images to plot the course of the catheter that releases the genetically engineered virus. “It’s just like a sniper’s bullet,” he said in an interview.¹ Once the virus has been inserted, the cancer killing begins. As Gromeier explains, “All human cancers develop a shield or shroud of protective measures that make them invisible to the immune system. By infecting the tumor, we are actually removing this protective shield.”¹ Once the immune system is alerted of the polio infection, it shifts into gear and attacks the cancerous cells, effectively neutralizing the tumor.

The polio virus clinical trial began in 2011 at Duke and still continues to date. However, the trial is only in its first phase, a human safety trial.  In order to produce a marketable, certified treatment, the trial must go through Phase II and III testing. The Food and Drug Administration is understandably very cautious in granting approval for medical treatments—the Duke group had to submit seven years’ worth of safety studies in monkey models to receive approval for the first human safety trial.⁷

LOOKING TO THE FUTURE

Success stories are impressive, especially for a Phase 1 trial that normally exists to simply test dosage. Take the example of Stephanie Lipscomb, a 24-year old nursing student who was diagnosed with glioblastoma in 2011. Though surgeons removed 98% of her tumor, the cancer quickly returned only a year later. With no other options, she enrolled in the Duke trial as its first patient. It was a risk, to be sure—Dr. Friedman himself admits, “We had no idea what it would do in the long haul.”¹ Though Lipscomb initially suffered some swelling, after 21 months her tumor shrank until it was completely gone. Despite these success stories, there have been mixed results. In fact, one patient who received a particularly potent dose of the virus experienced extreme inflammation causing swelling in her brain. Out of 22 patients, eleven died—most had doses of the virus that were extremely high. However, the eleven who survived have been in remission for over six months, unprecedented for recurrent glioblastoma.

In light of the Duke trials’ success, researchers are exploring using this technique of recombinant viruses to combat other forms of invasive cancer. Concurrently, the Gene and Virus Therapy Program at the Mayo Clinic has made several breakthroughs in clinical treatments, including a version of the measles virus to combat recurrent ovarian cancer and an adenovirus encoding a gene to combat prostate cancer.⁸ Moreover, the Mayo Clinic’s Department of Oncology has been using a modified version of the measles virus to combat glioblastoma, bringing the project from animal models to human Phase 1 testing in just under three years.⁹ A group in the UK completed a study in May demonstrating that using a genetically modified form of the herpes virus to treat melanoma, a type of skin cancer, causes an increase in survival rates.¹⁰ And researchers back at Duke are looking into using PVS-RIPO itself to treat other types of cancer, including prostate, lung, and colon cancers, and also determining how treatment differs for children since all trials thus far have treated adults.¹¹ Furthermore, research must be pursued for other aspects of treatment, beyond simply the viral vector—the Mayo clinic is investigating how to chaperone vectors to tumor sites inside protective cell carriers like macrophages or stem cells.⁸

A CURE FOR CANCER?

It is clear that this research is the start of a new and exciting age of cancer treatment. However, many caution against hailing this as the “cure for cancer.” A pressing concern is that high doses of the recombinant virus can cause massive swelling.¹² This is especially problematic in treating cancers like glioblastoma. However, Dr. Friedman emphasized that the point of this initial trial was to get the right dose—not to determine the virus’s effectiveness.¹

Though these are legitimate concerns, they are hallmark worries about cutting edge treatments. And it is almost certain that Stephanie Lipscomb was not thinking about the intellectual property law when she found out that her cancer was completely gone. “I wanted to cry with excitement,” she said in an interview with CBS.¹ Invasive cancer is still a difficult and dangerous disease. However, with innovative new research approaches like those involving viruses, we are certainly on the way to finding a cure.

Caroline Wechsler ‘19 is a freshman in Weld Hall.

Works Cited

1. Pelley, S. CBS News. Polio to treat cancer? Scott Pelley reports on Duke clinical trial. http://www.cbsnews.com/news/polio-cancer-treatment-duke-university-60-minutes-scott-pelley/ (accessed Oct. 5, 2015).
2. American Cancer Society. Cancer Facts and Figures 2015 (4-8). (2015).
3. National Institutes of Health. Cancer costs projected to reach at least $158 billion in 2020. http://www.nih.gov/news-events/news-releases/cancercosts-projected-reach-least-158-billion-2020 (accessed Oct. 5, 2015).
4. National Science Foundation. How do viruses attack cells? https://www.nsf.gov/news/overviews/biology/bio_q01.jsp (accessed Oct. 5, 2015).
5. Wessner, D. R. The Origins of Viruses. Nature Education 2010, 3(9), 37.
6. Rensselaer Polytechnic Institute. The Basics of Recombinant DNA. http://www.rpi.edu/dept/chem-eng/Biotech-Environ/Projects00/rdna/rdna.html (accessed Oct. 5, 2015).
7. Caba, J. Medical Daily. Once-Deadly Polio Virus Could End Up Curing Brain Cancer. http://www.medicaldaily.com/polio-virus-may-curebrain-cancer-thanks-genetic-re-engineering-327620 (accessed Oct. 5, 2015).
8. Mayo Clinic. Gene and Virus Therapy Program. http://www.mayo.edu/research/centers-programs/cancer-research/ (accessed Oct. 5, 2015).
9. Mayo Clinic. Neurosciences Update. [Online] 2012 9(1), 3. (accessed Oct. 5, 2015). [10]
10. Knapton, S. The Telegraph. Genetically engineered virus ‘cures’ patients of skin cancer. http://www.telegraph.co.uk/news/science/science-news/11631626/v.html (accessed October 5, 2015).
11. Preston Robert Tisch Brain Tumor Center at Duke. Targeting Cancer with Genetically Engineered Poliovirus (PVS-RIPO). http://www.cancer.duke.edu/btc/modules/research3/index.php?id=41 (accessed Oct. 5, 2015).
12. Kroll, D. Forbes. What ‘60 Minutes’ Got Right And Wrong On Duke’s Polio Virus Trial Against Glioblastoma. http://www.forbes.com/sites/davidkroll/2015/03/30/60-minutes-covers-dukes-polio-virus-clinical-trial-against-glioblastoma/ (accessed Oct. 5, 2015).