E. Antonio Chiocca, MD, PhD
Malignant gliomas are a set of tumors that arise in the brain. We do not know for sure what the cell of origin is, but we think it’s probably a cell that’s called a stem cell that goes awry and gives rise to these tumors.
Malignant glioma is a relatively generally term, it denotes tumors that tend to be very malignant, they grow in the brain by both dividing and causing a mass, as well as infiltrating to the brain. They don’t metastasize to the body like other cancers; they just metastasize in the brain itself.
The current standard of care for malignant glioma is to remove the tumor by surgery. We do what is called a gross total resection. That probably removes close to 95 to 98 percent of the active tumor that we can see but there’s a lot of microscopic disease that we sometimes don’t see on the MRI scan that still needs to be addressed.
After the tumor has been resected, for about six weeks, patients undergo concurrent chemotherapy with temozolomide and radiation therapy. Temozolomide is given as an oral drug and the radiation therapy is given to the area of the tumor resection and surrounding brain.
During this time period the patient is followed with MRI scans, fairly frequently, for six to eight weeks to make sure that the tumor doesn’t come back.
We’re very good at removing the main tumor mass, but really what sets up the tumor to come back is the tumor cells that invade and migrate throughout the brain and we don’t have very good ways of stopping this.
One of our areas of research that started at the bench side and has progressed all the way to the clinic has been to find new treatments for these tumors. One of the treatments involves common viruses, which we all think are pathogenic. But the one great thing about a virus is that it has evolved over the millennia to enter and infect the cells of your body in a very efficient fashion.
So the question is can we make a virus that’s going to do that, but only to the tumor cells and not to normal cells? And the answer is yes; we can engineer a virus, just like you engineer a drug, to become a tumor selective, tumor killing virus. So we’ve done that with one common virus, this is the virus that provokes cold sores in your mouth, called herpes simplex virus, type 1. The reason we chose this virus is because it’s a very efficient killer of cells, it can get in very rapidly, and destroy them fast.
The other nice thing about the herpes virus is that when the virus infects the tumor cells and destroys them, it not only does that but, because the virus is also very antigenic, the virus can also rev up or stimulate the immune response so it creates a vaccine-like effect.
This slide illustrates what an oncolytic virus will do to a tumor. The oncolytic virus has infected some of the tumor cells and the tumor cells that are infected are shown by the arrow on the far left. As that oncolytic virus propagates, in other words as it kills those tumors cells and makes lots of other viruses, it will infect other surrounding tumor cells. In the middle panel the tumor has turned completely blue because that virus has spread throughout the entire tumor. And as it does that, it kills off the tumor and by eight days, in the panel on the far right, it leaves a hole where the tumor was; however, normal brain is still there. So this is what we’d like to see happen with patients.
We have now engineered a new virus, based again on herpes, that we think is going to be very tumor selective for those cells that we call stem cells, the initial cells that cause these brain tumors. And we’re hoping to start a new clinical trial here at Brigham and Women’s Hospital and Dana-Farber Cancer Institute using one of these engineered herpes viruses.
In our laboratory we’re interested in not only trying to find new therapies against these tumors but also in understanding these tumors.
We have to remember that tumor cells don’t live by themselves in the brain, they have to interact with their micro-environment. They have to interact with blood vessels, because the blood vessels bring nourishment to the tumor, they have to interact with normal cells, such as astrocytes and neurons, to usurp their functions to migrate and infiltrate into the brain.
So for example, one of the factors we’re very interested in is a piece of genetic material called microRNA. MicroRNAs are new pieces of genetic material that were discovered recently and we’ve been trying to find out which microRNAs allow the tumor cells to communicate with their micro-environment.
One of the things we found is that tumor cells also release packets of information called exosomes, and they also allow the tumor cells to communicate with blood vessels, and other normal cells in the brain, so these blood vessels allow the tumor to do bad things in the brain.
I think in the future what will happen is when you come to surgery for your tumor, we’ll remove the tumor and we will be able to study it and sequence the tumor DNA. The tumor DNA basically provides the software information for the tumor cells to allow it to do what it does. We will also sequence the tumor’s microRNA, look at the exosomes, look at how they interact with the environment and then, based on that information, we can individualize treatment to each patient.
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