Making Progress in Glioblastoma

Making Progress in Glioblastoma

NINDS Director Walter J. Koroshetz and NCI Director Norman E. Sharpless

Nearly 24,000 people in the United States will receive a diagnosis of brain cancer this year. Among brain cancers, glioblastoma multiforme (GBM) is the most common in adults, the most lethal, and the hardest to treat. The 5-year survival rate for brain cancer is 33%; for GBM, it is only 15%. Although GBM rarely metastasizes outside the central nervous system, it’s a brain cancer without borders that slithers with ease throughout neural tissue.

May is Brain Tumor Awareness Month, an opportune time to increase awareness of the urgency to find effective treatments for people with brain tumors, especially GBM. 

While we can celebrate the tremendous progress we’ve made in understanding and treating many cancers, we owe it to all patients to also focus on cancers where we have had little or no success. GBM is one of those cancers that has been refractory to therapy to date.  The standard course of cancer treatment—remove the tumor by surgery, then kill the remaining cancer cells with radiation and/or chemotherapy—has proven to be minimally effective for GBM. We’ve seen too many patients and their families suffer while the brain tumor grew and successively robbed one neurological function after another.  

What makes GBM so uniquely resistant to standard cancer treatments? What new research can turn the tide and counter this resistance? These are exactly the questions NINDS and NCI hope to answer by funding and conducting innovative, rigorous research to help us better understand disease mechanisms and develop more effective treatments. Basic science—the foundation of discovery—is our best hope for finding these answers.

Fueled by basic research, the NINDS Division of Translational Research (DTR) and the Neuro-Oncology Branch, a joint program of the NCI Center for Cancer Research (CCR) and NINDS, are dedicated to bringing new investigational treatments to the point of clinical trial readiness.

One class of promising new treatments for glioblastoma that have recently made their way into clinical trials employs a strategy known as oncolytic virotherapy. A refinement of past gene therapy approaches, oncolytic virotherapy consists of administering cancer-killing (oncolytic) genes into a patient by packaging the genes in otherwise harmless viruses (virotherapy). These viruses can be modified to carry virtually any gene, allowing them to selectively kill cancerous cells. Viruses are selected based on their tropism, or affinity for infecting only certain types of cells, thus enabling these treatments to destroy cancerous cells without harming healthy ones.

When a virus infects a tumor cell, the virus continues to replicate until the cell explodes and dies. As the cancer cell is dying, it releases antigens, alerting the immune system to detect the cancer. This, in turn, triggers an immune response and enhances the cancer-fighting ability of the body’s innate immune system. Because oncolytic virotherapy harnesses the body’s immune system against the tumor, some in the field consider it to be a form of immunotherapy.

Highlighted below are four potential therapies for GBM that grew out of research supported by NINDS and NCI that are now being tested in patients. While these studies represent just a small sample of NINDS’ and NCI’s brain tumor research portfolios, they offer optimism about the future of GBM treatment.

  • Drs. Maria Castro and Pedro Lӧwenstein conducted a series of NINDS-funded experiments revealing how the brain’s immune system—normally ineffective against glioblastoma tumors—can be augmented by introducing two specific genes into the brain. One gene, thymidine kinase, kills dividing cancerous cells and allows the immune system to “taste” glioblastoma-specific antigens, while the other, Flt3L, summons immune cells, called dendritic cells. Acting synergistically, the two viruses recruit dendritic cells to the brain and equip them to seek and destroy the cancerous cells that make up the glioblastoma. The treatment was shown to significantly improve survival rates for glioblastoma-afflicted mice in the investigators’ NINDS-funded translational project. Now the nonprofit-funded Combined Cytotoxic and Immune-Stimulatory Therapy clinical trial aims to replicate this effect in patients undergoing surgery for glioblastoma.
  • In another NINDS translational research project utilizing oncolytic virotherapy, Dr. Maciej Lesniak’s team of researchers found that they could effectively shuttle cancer-killing viruses into the brain by packing them in neural stem cells, which are naturally inclined to migrate toward tumors. The neural stem cells produce many copies of the oncolytic virus, CRAd-S-pK7, and when they arrive at the glioblastoma, their viral payload goes to work—in this case, by interfering with cancerous cells’ DNA repair mechanisms. This innovative strategy significantly prolonged the survival of mice with glioblastoma and the same approach is currently being applied in Northwestern University’s clinical trial of virotherapy for glioblastoma. The team behind the clinical trial is hopeful that using these oncolytic, virus-loaded, neural stem cells will enhance the effectiveness of conventional radiotherapy and chemotherapy for patients with glioblastoma.
  • The NINDS translational research program also supported Dr. Noriyuki Kasahara in developing an elegant combination treatment approach to glioblastoma, whereby a viral gene is used to make cancerous cells selectively vulnerable to a systemically administered drug compound. First, a modified virus, Toca 511, delivers the gene for a yeast-derived enzyme to cancerous cells at the site of the glioblastoma. Then, the enzyme, which is only released in the Toca 511-infected cancerous cells, converts the otherwise inactive experimental drug, Toca FC, into an active form, which causes these cancerous cells to self-destruct. The treatment has already been tested in a small industry-funded clinical trial to verify its safety. Now, the larger Toca 5 clinical trial, supported by the Food & Drug Administration’s Orphan Products Clinical Trials Grants Program, will assess its effectiveness at destroying glioblastoma tumors and improving patient outcomes.
  • Dr. E.Antonio (Nino) Chiocca’s research group developed another approach to attacking glioblastoma—a therapeutic virus dubbed rQNestin34.5v.s. This oncolytic virus started out as herpes simplex virus type 1 (HSV1), but was genetically modified to only infect glioblastoma cells, sparing nearby healthy cells. The modified virus achieves this precise partition thanks to a specific segment of the genome that is highly active in glioblastoma cells, but dormant in healthy, mature brain cells. NINDS-supported translational studies of rQNestin34.5v.2 demonstrated that the virus was capable of infecting cancerous cells using the cells’ own molecular machinery to self-replicate and then killing the cells from the inside out, ultimately resulting in significantly improved outcomes in an animal model of glioblastoma. Now, investigators in the NCI-funded Treatment of Recurrent Malignant Glioma With rQNestin34.5v.2 clinical trial will determine whether the improvements seen in the translational project can be extended to glioblastoma patients.

These studies demonstrate a resurgence in gene therapy approaches to treat cancer and how such approaches have evolved with improved understanding of tumor and immune mechanisms. Earlier efforts sought to squelch immune responses, based on the belief that oncolytic viruses delivered to a tumor needed to be protected from the patient’s own immune system. In contrast, researchers now focus on strategies that selectively deliver gene therapies to tumors, and once there, mount a precisely targeted immune response that helps to kill cancerous cells.

In addition to oncoloytic viruses, other immune-based approaches are being broadly tested as treatments for GBM. In the Neuro-Oncology Branch, for example, Dr. Mark Gilbert and his colleagues are conducting early-phase clinical trials at the NIH Clinical Center using immune checkpoint inhibitors in combination with both standard therapies for GBM and with other immune-based treatments. Immune checkpoint inhibitors are the most heavily used immunotherapy treatments for cancer, having proven to be highly effective against advanced forms of lung, skin, bladder, and several other cancer types. The NCI researchers hope their work can expand that list to include GBM. Several other forms of immunotherapy, including vaccines and other cellular therapies, are being tested as potential GBM treatments. You can read more about them in this recent post on NCI’s research news blog, Cancer Currents.

While a number of immunotherapy-based clinical trials have failed to demonstrate success, we are definitely seeing some glimmers of hope, and scientists remain optimistic about the potential of immunotherapy for GBM. However, we know it’s going to take some time and more research to understand how the brain’s immune system operates, which appears to be quite different than the way other organs’ immune systems work.

NINDS and NCI also have encouraged the inclusion of brain tumor research within a new Immuno-Oncology Translation Network, established by NCI as part of the Beau Biden Cancer MoonshotSM and authorized by the 21st Century Cures Act. As described in recent funding opportunity announcements, the new collaborative network aims to accelerate progress toward immune-based treatments and prevention strategies for several types of cancer.

NCI is also exploring novel collaborations with extramural researchers and pharmaceutical partners, as well as international partners. As part of this effort, this month NCI’s Clinical Trials Advisory Committee established an Ad Hoc Glioblastoma Working Group, and NCI recently hosted a scientific workshop that included researchers, advocates, and others from the brain cancer community.

All of the efforts described above will help to stimulate more research on glioblastoma and accelerate progress. For patients living with brain tumors, it can’t come rapidly enough.

 

Other related links:

NINDS Brain and Spinal Tumors Information Page

NCI Brain Cancer Information Page

Wednesday, May 30, 2018