Yaron Moshel M.D., Ph.D, FAANS, a Neurosurgeon at New Jersey’s Atlantic Neurosurgical Specialists and co-director of the Gerald J. Glasser Brain Tumor Center at Overlook Medical Center in Summit, New Jersey, talks about a treatment for recurring brain tumors.
Interview conducted by Ivanhoe Broadcast News in February 2017.
First off, for someone like John let’s say if he would have a recurrence right, what would normally be his options for that?
Dr. Moshel: At the time of recurrence for someone like John it would be a tough case. Because his tumor is in a location that’s considered relatively inoperable, it was a challenge to even do the original surgery. But one of the options would be to go do a second surgery. Another option would be to do Cyberknife Radiosurgery which is a form of pinpoint radiation. The other options are chemotherapeutic options for which unfortunately for his particular tumor there really aren’t a lot of good medical treatment options.
He had what procedure done initially?
Dr. Moshel: He had a craniotomy which simply refers to the opening up of the skull and allows acces to a brain tumor for the operation. His operation gets very technical and specific because of the location of his tumor. His tumor was located within the upper part of the brain stem know as the midbrain. That the upper part of the brain stem controls a lot of key functions, especially eye movement and your ability to focus and move your eyes. Also a lot of basic body functions that keep you alive and making sure you’re conscious. The seat of all these functions is where the tumor was located. The operation we did was complicated because of the location and difficulty in accessing this deep seated location. We navigated around certain natural corridors in the brain to allow us to kind of sneak into that spot and sneak out. That’s really the idea with surgery in these delicate areas you kind of want to get in there do the surgery without damaging anything and get out as quickly as you can.
Now a few questions about the Toca 5 clinical trial? Simply put what are the statistical outcomes? Because I had read articles that illustrate how successful this seems to be so far.
Dr. Moshel: Well, Toca 5 specifically is an international clinical trial that is currently ongoing but closed to enrollment. The purpose of that trial was to take patients who have a very aggressive tumor called a glioblastoma or an anaplastic astrocytoma, which is a slightly less aggressive version of that tumor. After undergoing surgery and chemotherapy these tumor often come back and patients don’t really have a lot of good treatment options. There are a couple of drugs that are out there but still the survival rates have not been great. The Toca 5 concept was to sort of sabotage the tumor cells. What we would do is inject a live virus into the tumor at the time of surgery. It’s a unique study in that we are actually injecting a true living virus into the patient. The idea is that virus would propagate and infect all the tumor cells. Once it got into the tumor cells it would copy a gene into the tumor cell rendering it susceptible to a drug that otherwise would not have been effective which is given in cycles after surgery. The other component of it is simply the tumor cell is getting infected by a virus in a specific fashion causing the tumor cell to die. That reaction triggers a large immune response activitating the body’s own immune system against the tumor and breaking down the immune shield that most of these tumors establish to keep the immune system out. All of this falls under the category of immunotherapy. What they found with the Phase 1 study of the Toca 5 is that the survival rates in patients with recurrent tumors were close to double compared to historical controls with standard chemotherapy. That was a key finding and that’s what prompted this study which was a Phase II study, which was a multicenter randomized open label study. The patients were randomized to select out bias in the study and compared to investigators choice of a single agent standard chemotherapy agent.
But again, when you say, repeat for me please the part about double the—-
Dr. Moshel: Roughly the survival time increased from what on average was a seven-month survival time to close to a 14 month survival time, for people with recurrent tumors, which in that world with these tumors is a huge change. Its an impressive result because they were studying the effect of Toca 5 immunotherapy while those patients were not getting any conventional chemotherapy. It wasn’t layered on top of existing chemotherapy. People were getting either the study drug or standard therapy.
Okay but Toca 5 immunotherapy. This is done in conjunction with surgery if somebody has recurrence– is it only for recurrence and not first time diagnosis?
Dr. Moshel: The study right now is for recurrent tumors. The hope is that if this is successful, one day the company could potentially open a trial for patients with newly diagnosed tumors. Maybe if success is proven it could one day be part of the upfront treatment for patients. But that has to be proven through extensive studies. Typically we start with patients that have recurrent tumors because our options are so limited in that population.
It’s done in conjunction with surgery?
Dr. Moshel: Yes. Tocagen is a virus that is done in conjunction with surgery. At the time of surgery we remove the tumor and in the margin of where the tumor was removed we inject the virus into the surrounding brain tissue to chase any tumor cells that are left behind.
For someone like John if he were God forbid to have a situation where he needed treatment again how would this be beneficial to somebody like him?
Dr. Moshel: Well, someone like John has a very unique tumor and a lot of the studies that are out there they try to maximize their chances of succes so they are geared towards patients that have the most common kinds of tumors and in the most common locations. John’s unique in that his tumor was in the mid-brain. It’s a tough place to go back in and do surgery again. He might be a candidate for immunotherapy one day but not one where you would inject a virus directly into the that part of the brain. There are other types of immunotherapy trials that he could potentially be a candidate for where the treatment is administered systemically. There are especially a lot of new immunotherapy drugs and antibodies that are being manufactured for which he might be a candidate for.
What is immunotherapy generally in and of itself? What does immunotherapy mean, because it’s a commonly used term?
Dr. Moshel: It’s a generic term, there’s been a lot of progress with this and with the study of tumors and how the tumors relate to the immune system in the last 20 years. There have been all sorts to attempts to study this over the years. When it comes to brain tumors specifically, it stems from some early observations that patients who had tumors removed and went on to have infections after surgery, normally a complication of surgery. Those patients for some reason thought to do better in terms of survival. It was never really studied rigorously but that triggered a lot of the research with the immune system and the brain tumors. It turns out the brain tumors are very smart. What they do is they set up this defensive shield around themselves. The tumors secrete chemicals that block your immune system from seeing the tumor. It really is a robust immune shield that the tumors have developed surrounding them. In immunotherapy we are basically trying to break this shield. Your own immune system would attack the tumor if it could, but it’s being suppressed by this shield. There are a number of strategies. One strategy is to overdrive the immune system and break down this shield. We use that for example with brain tumor vaccines. We would vaccinate people against their tumor. That’s a trial that we had going on here for several years and the idea is there to overdrive the immune system so that it can overcome the shield. Toca 5 is another example, where we create a big inflammatory response by killing these tumor cells. Sneak in the tumor with the virus like a Trojan horse, copy this gene in there that activates an innocuous compound into powerful chemotherapy, and try to break down this shield to allow the immune system to fight the tumor. The whole other strategy that’s out there and is often advertised on TV now is the use of certain drugs or antibodies that are being manufactured by pharmaceutical companies that will actually block the chemicals that are secreted by the tumor to create the shield. This strategy is being used in melanoma, lung cancer, and renal cell cancer. We’re still studying it in brain tumors. But those are the two strategies it’ about breaking down the shield that the tumor sets up. You can overdrive it by creating a lot of inflammation and activating the immune system against the tumor. You can also try to block those chemical messengers. We’re going to be studying both of them. There are trials that are going to come out where were using both approaches in the same patient at same time. That’s the idea of immunotherapy.
Finally, how is immunotherapy an alternative for people that either seemed like they would have had no other option, or would have very risky options that may be wouldn’t be worth pursuing. How would you sum up for people about how big of an impact this has in your world of brain tumor oncology?
Dr. Moshel: Well, we’re all very excited about immunotherapy in general and in oncology as a whole. When it comes to brain tumors some of these brain tumors are extremely aggressive. We’ve been trying for decades to come up with agents to help patients with these tumors. We’ve seen some very interesting results with immunotherapy, especially the brain tumor vaccine approaches and novel approaches such as Toca 5 where we inject a virus into the brain. We’re seeing some really interesting and dramatic results. We’re very excited and I think this research is very important. The ultimate cure for these tumors it’s not going to be a surgical cure. In surgery we can only removes so much of a tumor and not down to the last cell. These tumors have cells that migrate throughout the brain that we kind of have to chase down. That’s not something that a surgeon can do. That’s something that’s going to have to be done by a small molecule that travels throughout the brain or by your own immune system that will travel throughout the brain and catch these tumor cells. We’re pretty excited about it and its still an emerging field.
END OF INTERVIEW
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