Neural stem cells: On the frontier of brain cancer therapy

Gliomas, a type of tumor that grows in the brain, are very difficult to treat successfully due to their complex nature. That might not always be the case.

First some background: The most aggressive and common type of primary brain tumor in adults is glioblastoma. Although the brain tumor mass can often be removed surgically, complete resection (or removal) of all the tumor cells is virtually impossible due to the invasive nature of glioblastoma, and tumor recurrence is the norm.

Karen S. Aboody, M.D., professor in the Department of Neurosciences and Division of Neurosurgery at City of Hope, believes the key to recurrence prevention lies in special cells called neural stem cells. She has collaborated with Jana Portnow, M.D., associate professor of Medical Oncology and associate director of the Brain Tumor Program at City of Hope, on a Federal Drug Administration-approved clinical trial that aims to deliver drugs to  brain tumor cells without damaging healthy tissue.

Where is brain tumor research going, in general – and how is City of Hope’s approach different?

Portnow: Unfortunately, as far as treatment for glioblastoma goes, there haven’t been any major breakthroughs for a long time — not since we learned from a pivotal study published in 2005 that temozolomide added to radiation therapy improves survival in patients with newly diagnosed glioblastoma. In that study, the percentage of patients alive at two years from diagnosis more than doubled – from 10 to 25 percent. However, I think everyone would agree that we have a long way to go in terms of making a significant impact on this disease.

But brain tumor research is advancing. At City of Hope, we are studying how neural stem cells can be used to treat cancer. We are about to open a phase I study of neural stem cells, which are directly administered into the brains of patients with recurrent glioblastoma. These neural stem cells have been modified to carry a protein that converts aprodrug to an active chemotherapy agent at tumor sites in the brain.

Aboody: With the neural stem cell therapy, we found that neural stem cells have a natural ability to seek out and find invasive brain tumor cells. That is why we are using them as delivery vehicles to target chemotherapy directly to the tumor cells. We have genetically modified these neural stem cells to produce chemotherapy locally at sites of tumor in the brain.

Rather than putting chemotherapy through the whole body and possibly causing significant side effects that affect a person’s quality of life, the neural stem cells only produce active chemotherapy at the sites of tumor, killing surrounding tumor cells. As a result, we expect minimal side effects while still getting the concentrated amount of chemotherapy only to the tumor site.

What will this clinical trial seek to establish?

Portnow: Our first in-human clinical trial of these neural stem cells demonstrated that treatment with neural stem cells and the oral prodrug flucytosine (5-FC) was well-tolerated by study patients.

Aboody: And we were able to show proof of concept — that the stem cells were converting 5-FC to the activechemotherapeutic agent, 5-fluorouracil (5-FU) in the brain.

Portnow: So now we are ready to move onto the next step, which is to do a phase I study to determine the maximum tolerated dose of neural stem cells that can be safely administered directly into the brain. In our-first-in human study, the FDA only allowed us to give patients one round of neural stem cells and 5-FC. Based on the encouraging safety data from this study, the next study will not only determine how many neural stem cells we can give, but it will also look at the feasibility of administering repeat doses of the neural stem cells. A catheter will be placed in the brain at time of surgery, and it will be used to administer subsequent doses of neural stem cells directly into the brain every two weeks (followed each time by a seven day course of 5-FC, which is taken by mouth), for as long as the patient is tolerating the treatment well and there is no evidence of tumor growth on MRIs, which will be performed every two months.

Who would be a candidate for this trial? And when will it start?

Portnow: Patients with recurrent high-grade gliomas who are planning to undergo surgery — either to remove or biopsy tumor.

Aboody: This phase I study will be open for patient enrollment within the next week or so.

City of Hope is known for its collaboration between research scientists and physicians. How does that collaboration work in your case?

Aboody: The only way to effectively translate science from the laboratory to the patients is in collaboration. Scientists need input from clinicians about what they see in the patients — what is and is not working — so that we can modify our experiments to address the obstacles that they are facing with their patients’ treatment.

Portnow: Karen and I have a great partnership. We have worked together very closely for years now. Our initial collaboration was for the first-in-human study of genetically modified neural stem cells used as an anti-cancer treatment. Now we are just about to start a formal phase I study, and we will have other neural stem cell-based studies coming for patients with brain tumors.

How do you think brain tumor treatment will have progressed in the next five or 10 years?

Portnow: There are a couple of vaccine studies in patients with newly diagnosed glioblastoma going on right now that are in phase III testing. Most investigational treatments do not even make it to phase III testing. I certainly look forward to seeing the results of those vaccine studies, which should be reported in the next five years.

Aboody: It is important to note that we all learn from each other’s trials. We watch the results of these current new therapies to see if there is potential to maybe combine them with neural stem cells to optimize efficacy. For example, we have optimized stem cell preparation so it only involves thawing the frozen vial of cells, rinsing them and then infusing them into the patient. We have minimized any manipulation so that if we do multiple center trials in the future, all we have to do is ship the vial of cells; they thaw it, rinse it and administer it.

Portnow: The process is simplified to the point that if these stem cells do turn out to be a worthwhile therapy, it will be something that can be available and done at other centers besides City of Hope.

What inspires you both to do what you do every day?

Portnow: I love my brain tumor patients. They struggle heroically against an incurable tumor, and it is an honor to be able to walk with them through this chapter in their lives. I think it is really important as an oncologist to be a part of working toward finding the cure. That is why I enjoy doing this research; we have to find better treatments for brain tumors.

Aboody: Many years ago, I learned that my sister-in-law was diagnosed with breast cancer that metastasized to her brain. In addition to the cancer itself, the side effects of the cancer treatments took a toll on her life. If I could find a way to target therapy directly to the tumor, and not have to put the patients through this systemic chemotherapy, then that would be a big advancement in cancer treatment.