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Stem Cells: A Therapeutic Approach for Brain Tumors

Melanie Cole (Host): Cancers of the brain continue to be one of the greatest medical challenges and yet finding successful treatments for brain tumors remains one of the more exciting areas of medicine. My guest today is Dr. Maciej Lesniak. He’s the Chair of Neurosurgery at Northwestern Medicine. Dr. Lesniak, let’s start with a little bit about the state of therapies that have been available for brain tumors and have been practiced for the last 20 years or so.

Dr. Maciej Lesniak (Guest): So as you eloquently pointed out, brain cancer is one of the deadliest forms of human disease, and during the last 100 years there have only been three FDA approved treatments. None of them cure brain cancer, however, each one of them has been shown through prospective randomized clinical trials to make a difference for patients with brain tumors. The first one was a study out of Hopkins in 1995 that looked at delivery of gliadel wafers to brain tumor resection cavity, and then two other forms of therapy, which have recently been approved over the last 15 to 20 years or so stemmed actually from the work of Roger Stupp, who is the Director of Neural Oncology here at Northwestern and those two works involved the use of chemotherapy such as temozolomide which is the standard of care now for patients with brain cancer around the world, as well as the use of tumor treating fields, which in the last year or so have also been approved by the FDA for the treatment of patients with brain cancer. So in a nutshell it’s a devastating disease. We’ve had three potentially interesting therapeutic options, none of which have resulted in a cure, but all of which have been shown to prolong survival, and so in light of this, there’s a lot of ongoing interest in scientific endeavors to make this disease go away and how to improve it through new and clinical work.

Host: So speak about some of that new and clinical work, give us a little brief overview of the use of stem cells as an approach to treating brain tumors, and how this form of therapy is breaking onto the scene.

Dr. Lesniak: There are many different approaches for cancer period. When it comes to brain tumors especially they still range from different chemotherapy agents to immunotherapy to gene therapy to nanotechnology to stem cell work. I think stem cells have potentially been very interesting because of their ability to travel in the human brain. So in the last decade or so researchers around the world, including our own lab have shown that these stem cells, which are basically early progenitor cells, especially stem cells that originate from the brain, so neural stem cells, have an amazing ability to travel throughout the human brain and they can do so within hours to days. What it also means is that when you inject them in animal models and some early human work, these stem cells appear to seek out areas of injury, and that can be broadly defined as areas of inflammation such as multiple sclerosis, areas of stroke which can happen in patients, or in the research that we’re doing at Northwestern in the setting of brain cancer. So stem cells are quite adapt at traveling to invasive tumor cells in the brain, which are not always visible on an MRI. Often times what we see on MRI is the tip of the iceberg, but the allure of these stem cells is their ability to seek out and colocalize with some of these more invasive tumor cells that we don’t even have the imaging capability to see, and so in light of that you can imagine different scenarios where the stem cells can be used to deliver agents. So they can deliver cargo. Imagine sort of a concept of a missile and a warhead. It’s the same thing here. Stem cells can be viewed as a missile to deliver a warhead. The warhead can be a particle such as a nanoparticle, it can be a gene therapy agent, it can be a multitude of other potential therapeutic options that will allow enhanced delivery of these agents to the brain, which is really the goal of most modern thinking about brain tumor therapy specifically when it comes to stem cells. One of the innovative works that we’ve done here, along actually with my collaborator, Karen Aboody, who is at City of Hope, has been to use stem cells to delivery oncolytic viruses. So oncolytic viruses are viruses that have been engineered to selectively replicate and kill brain cancer cells. We load these viruses onto the stem cells, which then travel to these invasive areas of the brain where we can’t see the tumor where they deliver this virus, which then infects those cells and destroys them. This is one of the more innovative clinical trial works involving stem cells that’s going on in the world today.

Host: So that’s fascinating. So to just summarize a little, one of the goals of this ongoing research is not only to understand the function of these brain stem cells, doctor, and how they may play a role in the development of brain tumors, but to ultimately genetically engineer these cells, as you say, with viruses to fight brain cancer. How do you see this as a breakthrough in your clinical specialty? Tell us about the trials that you’re doing.

Dr. Lesniak: So I think it’s important to differentiate two things that exist in this field. One is cancer stem cells versus progenitor stem cells. So cancer stem cells are often times described as stem cells that originate from the cancer themselves, and they’re responsible for the growth and return and progression of the cancer because they’re very resistant to chemo and radiation therapy. That’s one subset. What we’re talking about here now is the use of early progenitor cells such as normal human stem cells, but to use them to delivery therapeutic agents to cancer cells including cancer stem cells. As I briefly alluded to before, we have worked with a human neural stem cell line, which was actually developed by Karen Aboody at City of Hope, and we have characterized the ability of this human neural stem cell line to be infected by this norovirus that was created by us in collaboration with David Cugell of Washington University in St. Louis, and so when we married these two agents together, which is the stem cells and this virus, we have shown through probably a decade worth of research that in animal models of brain cancer, when we use this therapy, along with what is considered the standard of care, which is currently chemo and radiation therapy, we can get a synergistic benefit and some of these animals really survive the cancer and do much better than with individual therapies alone. So it took us about ten years to get to this point, and about two years ago we approached the Food and Drug Administration about letting us use this in patients for the first time in the world, and what was also unique about this approach is that a lot of times when it comes to brain tumor clinical trials, the FDA has allowed clinical trials to occur in the setting of recurrent disease, meaning you’ve already been treated once, and let’s say 6 to 12 months later the cancer comes back despite all the therapy, and then you have the option to enroll them in another clinical trial. Well this was different. This was the first time in the history that the FDA said, you know what we’re not going to wait for the cancer to fail every therapy. We’re not going to wait for it to fail radiation, chemo, and surgery. We’re going to let you use this therapy up front at the time of the initial surgery. So go ahead, get the tumor out, and at the time of the surgery inject these stem cells that are loaded with this virus, and the follow that up with the standard of care, which is chemo and radiation therapy because you have showed that the synergy that exists between these stem cells, the virus, the chemo and radiation is better than individual therapy alone. So this was the first time in the history of gene therapy that we were allowed to do something like that, and about a year ago, well in June of 2018, we opened this clinical trial here at Northwestern, and recently we opened it also at City of Hope in California.

Host: That’s fascinating Dr. Lesniak, which patients might be candidates? And are there any indications for institution with this – is there anyone that – tell us a little bit about patient selection and what you’re looking for.

Dr. Lesniak: Yes so this trial is designed for adult patients, meaning patients who are 18 or older. It does not involved at this stage the pediatric population, which arbitrability is defined as patients younger than 18. Anybody who is newly diagnosed with brain cancer is eligible. However, that brain cancer is restricted to patients with what we call grade 3 or higher astrocytoma. So this has to be a tumor that originates in the brain rather than metastatic cancer that can spread to the brain. In other words, this is not a trial for patients with breast or lung cancer that has spread to the brain. This is a trial for patients like Ted Kennedy or John McCain who were diagnosed with a primary cancer that arose in the brain. These cancers tend to be graded by a pathologist on the scale of one to four. One being more benign behaving and four, one of the most aggressive ones that exist in mankind. So we can enroll patients who are grade three or higher, at the time of the initial pathology in this trial. Now the key to it, it can only be done here at this point as well as at City of Hope because that’s where the FDA allowed the trial to be opened for the purposes of some of this early stage one clinical trial data. This is a stage one clinical trial, which means it is looking at dose escalation. We are enrolling different cohorts of patients to see if there is toxicity as we increase the number of stem cells as well as the virus that’s delivered to the brain. So far we have treated 9 patients and we have not seen any significant toxicity which would allow us to establish what’s called a maximum tolerated dose. In fact, in doses up to 150,000 million neural stem cells injected into the human brain. We have not seen any toxicity which would prevent us from continuing with this trial.

Host: And this approach can help decrease the toxic side effects to normal tissues, yes? To improve the patient’s quality of life. Tell us a little – because you’re giving a virus as well. Do you have some predictors of treatment response?

Dr. Lesniak: So when you do a phrase 1 trial, it really looks at the toxicity because you want to establish the highest possible dose, which can subsequently be used in a larger clinical trial that can answer information about statistical benefit to patients. So at this stage of the game we’re not really looking at survival although we are proactively following the patient who had received it, to see if whether the small number of patients appear to be doing better than historical controls, but from a scientific standpoint, that trial that would answer that question would be the trial that you would enroll 200-300 patients at multiple institutions around the world and then follow them over time and then do the statistics to see if there is a benefit.

Host: How can physicians learn more or refer their patients to your trials, doctor.

Dr. Lesniak: Well I think one of the things, of course word of mouth, but beyond that you know Northwestern Medicine is I think a national leader in brain cancer care. Recently the National Cancer Institute actually awarded us a SPORE grant, which stands for specialized program of organized research excellence and that is a multimillion dollar grant that basically acknowledges a national expertise in a specific area. There are only four other places in the United States that are designed by the National Cancer Institute as such institutions and we’re one of them. So I think for people in the Midwest, this is really the only place that has been designated by the NCI as one of those places. The reason why this designation exists is because of the robust science, the expertise, and the clinical trials that are offered to patients at Northwestern which originate from our own work and not necessarily work originating from the pharmaceutical industry to really champion and move the field forward. So patients can learn of course about this on our website, which is Northwestern Neurosurgery website, the Malnati Brain Tumor Institute website. Information about clinical trials is available through clinicaltrials.gov, as well as by reaching out directly to me and being in contact about what may be appropriate for any of the patients that are being taken care of in the community.

Host: Thank you so much Dr. Lesniak for coming on and speaking about this fascinating topic and your clinical trial, and I hope that you’ll come on again and let us know how it’s going. Thank you again so much. For more information on the latest advances in medicine, please visit nm.org, that’s nm.org. This is Melanie Cole, thanks so much for tuning in.