How Can We Kill Brain Tumors? Try Getting Them Sick With a 'Cold'
When you get a cold, each tiny virus infiltrates the wall of an unlucky cell, sheds its outer coating, and travels along the cell's inner scaffolding to the nucleus. Once there, surrounded by the cell's DNA-replicating machinery, the virus releases its DNA. With the cold virus, it rarely damages your own DNA, but it commandeers the nearby molecular factories to churn out more copies of itself. Eventually, the newly manufactured machines burst out of the cell, destroying it.
For the common cold virus, more formally known as adenovirus, it's a brutal process that evolved alongside human evolution over the course of millions of years. The viruses are precisely tuned to invade and repurpose as many human cells as possible before being caught - and consumed - by the immune system. It's a good thing your immune system is primed to kill the viruses, or eventually you wouldn't have any cells left.
Now consider what would happen if oncologists could commandeer the viruses, and use them to attack cells we actually want to destroy: cancer cells.
Making cancer sick
After decades of fighting cancer on its own terms, oncologists like myself are using viruses as the core of experimental treatments to attack brain cancer.
Building on years of research, clinical teams across the country are testing that approach using a variant of the cold virus, DNX-2401. Unlike normal adenovirus, chemical engineers at DNAtrix, in Houston, Texas, use a modified DNX-2401 initially developed at MD Anderson Cancer Center to attack cancer cells instead of healthy tissues.
While one would hope that the virus completely infects and destroys every cancer cell, the body is complex, and not every cell is vulnerable to attack - especially cancer cells, which have a range of molecular tools to keep viruses, and the immune system, at bay. The cells can sometimes go into stasis and not allow the virus to break them up, or the immune system may still not recognize the virus laden tumor cells.
So in addition to injecting the virus into tumors, researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James), along with other scientists, are exploring injecting other medicines into the body to help the immune system find the cells amidst the noise and catch any that initially escape. In studies with mice and early trials with people, the results are promising. In some patients the approach appeared to be very effective, possibly because the virus started the killing of the cancer cells and the immune system learned to kill virus-infected cancer cells long term.
The concept is similar to how your body will always hunt the flu virus when you get your flu shot, which has bits of the virus protein to activate the immune cells – the immune system is now on alert. If we can make cancer look like an infection, perhaps the immune system can take care of it like it would the common cold.
Killing cancer before it harms the mind
When caught late, cancers of all kinds can be debilitating. But brain cancers, because of the damage they inflict to motor skills and the mind, are unique.
The brain is a delicately precious organ. Brain tumors are quick to cause damage and difficult to treat. You can have a mass in your abdomen the size of a football, and you can walk around with it, but that luxury does not exist for the brain.
The skull is a closed space, and brain tumors tend to spread out and wind their way into surrounding tissues, disrupting the brain's functions. Even more challenging, the organ is designed to keep foreign bodies out, because of something doctors call the blood-brain barrier. That barrier is a big obstacle to getting cancer-fighting drugs to a brain tumor site.
While secondary brain tumors, which come from cancer cells that originating elsewhere in the body, are the most common, tumors that originate and generally remain in the brain (primary brain tumors) can be more deadly.
According to the most recent brain-tumor statistics, this year doctors will diagnose at least 78,000 primary brain tumors. Of those, nearly a third will be malignant — not spreading beyond the brain, but reaching deeply into and around the tissues that surround them. Those patients will join nearly 700,000 Americans currently living with a primary brain or central nervous system tumor, of whom nearly 17,000 will likely not survive the year.
As brain cancers progress, the lives of these people are affected deeply by the condition. It can derail life – the tumors can change the person that you were.
As doctors, we live through these experiences with the patients. Without a fight that goes beyond the usual, without a clear understanding of the complexity, it would be easy to lose hope. That is why so many experts from so many disciplines are coming together to test new treatment approaches – ideas that, at first, seem almost fanciful.
For a sophisticated threat, a sophisticated response
One can think of cancer as evolution in fast forward. The cells are trying to survive against many odds, and in many ways succeeding when treatments fail.
By sending chemical signals out into the body to keep the immune system from finding them, cancer cells are actually usurping life's machinery to try to become immortal, keeping hidden and well fed. This is not a trivial fight. The goal for oncology is to tease out the intricacies of the disease, and try to disable it.
During the last decade, a range of studies have provided tremendous insight into one of the most dangerous brain tumor types, glioblastoma. These cancers emerge from the glial cells, which form the brain's supportive tissue.
At the heart of the new breakthroughs has been genetic profiling, and glioblastomas were the first tumors studies in the U.S. National Institute of Health (NIH) Cancer Genome Atlas. Those genes have revealed that within any one class of tumor, many types exist, each with different behaviors.
Understanding has now grown from recognizing the appearance and location of tumors to mastering how genomes reveal differences — and weaknesses — among them. Doctors need approaches that can work for a range of targets, and that's where treatments like viruses stand out.
Until recently, brain cancer treatments relied on limited tools, and provided little hope. My colleagues and I can now use technology to delve into the underlying biology as never before, to see the inner workings of tumors and then target them with a range of treatments.
Here at the OSUCCC – James we have a robust team of experts working with collaborators around the country to study several viruses, each a nanomachine with its own specialized weapons to attack brain cancer.
In addition to the adenovirus study, my Ohio State colleague and neurosurgeon Dr. James Elder is working with another partner (Tocagen) to investigate using a retrovirus to target brain tumors. Here, the idea is to work with viruses engineered to preferentially divide in tumor cells to produce a protein that can activate chemotherapy drug in an attempt to fight the cancer's defenses from every angle. Also, Balveen Kaur, PhD, is doing ground-breaking research using a different virus -- a herpes virus -- to exploit weaknesses in the tumor cells and to work with chemotherapies to eliminate tumor cells. Virus-only approaches have been in trials with patients before, but these latest trials using the virus combined with other drugs are brand new.
Cancer treatment goes viral
For two of the ongoing trials, my collaborators and I are working with DNX-2401. In a Phase I clinical study targeting glioblastoma and gliosarcoma brain tumors - conducted in close collaboration with MD Anderson Cancer Center, Baylor University and Moffitt Cancer Center—we're treating patients at Ohio State with both the modified virus and an injected boost of the protein interferon gamma, one of the molecules the immune system uses to tag viruses for attack.
We're also conducting a Phase II clinical study targeting a wider range of brain cancers - in this effort, partnered with University of Arkansas for Medical Sciences, Weill-Cornell Medicine New York-Presbyterian and Huntsman Cancer Institute in Utah pairing DNX-2401 with pembrolizumab, a molecule that helps block one of cancer's "cloaking" tricks.
These treatments can reactivate the immune system to fight cancer cells; however, sometimes that can also cause unwanted inflammation with side effects that can affect various organs in the body and occasionally the body’s hormonal system. Fortunately, these have been uncommon.
At every stage of the trials, we continue to look for common themes that can lead us to the next step, and we're getting closer and closer to a more complete understanding of the processes taking place — it's an incredibly rewarding time to be in the field.
Because cancer is so complex, for each trial at Ohio State we assemble a team of specialists to develop, execute, and monitor treatments. Our brain cancer subspecialists span a wide range of disciplines, from neuro-oncologists and radiation oncologists to neurosurgeons, neuroradiologist, neuropathologists, research scientists and others — all specializing in brain cancer (and only brain cancer) research, detection, treatment and cures. The end goal is to not just focus on therapy, but also quality of life.
Part of quality of life is coming to terms with the changes that a diagnosis of cancer brings. While built upon powerful ideas, the treatments are still evolving, and none is yet a certain cure. Patients ask me about life expectancy — I can tell them the average survival based on the many research studies that have been done; but I do not know if any patent fits that average. I now tell them that nobody can predict a person’s survival – I've been wrong too many times to offer it. I tell them I am with them for the long haul and that we will fight together for the best outcome our treatments can provide – while keeping it meaningful with quality of life and making sure they are not simply exposed to the side effects of treatments that don’t work.
I am optimistic that we're on the path toward a victory in a war that is being won one battle at a time, but we've moved past a time when the war was one-sided, with the cancer winning. As oncologists, we have to face the fact that many of our patients and their families have devastating consequences from a brain cancer diagnosis and the course of the disease. That we find ourselves making headway with the promise of the new research and the possibility of new treatments, and the incredible bravery of the patients who walk this walk, is the reason we can actually can get up and go back to work each day and fight again.
Dr. Vinay Puduvalli - The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James)