11/24/16: GLIOBLASTOMA: The Use of Poliovirus and Other Immunotherapies in Treatment of Deadly Brain Tumor

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Patients with glioblastoma, the most common malignant brain tumor in adults, typically survive fewer than 15 months after their diagnosis. Glioblastoma, also called glioblastoma multiforme, GBM, and grade IV astrocytoma, grows and spreads aggressively. It is the most severe form of astrocytoma, a primary tumor of the central nervous system that develops from small, star-shaped cells called astrocytes. 

Standard treatment for glioblastoma has long included: 1) surgical removal of as much as the tumor as is possible; and 2) radiation therapy, used alone or with chemotherapy. Increasingly, however, patients are being treated with radiation and a targeted immunotherapy in lieu of chemo.  

Much of today’s cancer research is focused on developing new targeted drug therapies that work by ramping up a patient’s immune system to do battle with cancer cells. If you or a loved one has been diagnosed with glioblastoma, and undergone surgery and radiation, your next step in life-extending treatment (which you may have already initiated) is to make an appointment with a cancer center where immunotherapy trials are occurring. I would look first at the Duke Cancer Institute (Duke), the Johns Hopkins Kimmel Comprehensive Cancer Center, or the National Cancer Institute (NCI), but any cancer center that is part of the NCI network should be able to help you.   

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GBM SYMPTOMS

I know two people who were diagnosed recently with glioblastoma, which is called a primary brain tumor because it originates in the brain and is not a metastasis from elsewhere. In both cases, you could say: “Gee, she seemed fine just months before her diagnosis.”

This cancer grows very fast.

Glioblastoma symptoms vary depending on the type, size, location, and extent of the tumor, as well as the health and age of the patient. The part of the brain that is involved (typically in the cerebrum, the brain’s epicenter) determines the functional system that the tumor affects. According to the Cancer Treatment Centers of America, symptoms may include:

*Persistent headaches

*Double or blurred vision

*Nausea

*Vomiting

*Loss of appetite

*Changes in mood or personality

*Changes in ability to think and learn

*Memory loss

*New onset of seizures

*Muscle weakness

*Speech difficulty

The symptoms may seem stroke-like to you or attributable to depression or another more common malady. A brain tumor is certainly not what you think of when your 70-year-old mother or spouse starts having headaches or cognitive difficulties. Unfortunately, the sudden symptoms of glioblastoma can worsen rapidly and lead to unconsciousness.    

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POLIOVIRUS THERAPY

You may have heard about the experimental poliovirus therapy for brain tumors developed at Duke. “60 Minutes” broadcast a well-publicized, if over-hyped, program in spring 2015 about the results of the first clinical trial of this therapy, which was a phase I trial, designed to test for safety and optimum dosage, NOT efficacy (effectiveness).  

After observing nearly 20 years ago that cancer cells have a receptor that the poliovirus fits into “like a key into a lock,” Duke molecular biologist Dr. Matthias Gromeier set about figuring out how he could “tame” the virus, and use it to kill brain tumors, according to the article, “Can Scientists Really Harness the Poliovirus to Kill Cancer?” by Angela Spivey in Duke’s fall 2016 issue of “Breakthroughs.”

The German-educated Gromeier successfully engineered a way to make the deadly poliovirus harmless, except to cancer cells. He replaced a segment of the poliovirus’s RNA genome with a corresponding piece from a human rhinovirus, a type of virus that causes the common cold. His invention is known as the PVS-RIPO poliovirus.

Gromeier subsequently spent years testing the PVS-RIPO poliovirus in animals to ensure that it couldn’t cause poliomyelitis, the childhood paralytic disease that threatened 20th-century Americans before development and distribution of the Salk vaccine. For the 2012 phase I trial, upon which “60 Minutes” reported, Duke clinicians injected the modified poliovirus into the tumors of 24 patients with recurrent glioblastoma, meaning their cancer had returned after surgery and treatment.

Of the 24 patients, 11 appeared three years later to be doing well with no disease progression and two of them were “cancer-free,” meaning they were in remission. The remaining 13 had died, among them some who had “debilitating inflammatory reactions” to the virus, according to “Breakthroughs,” which noted that controlling inflammation by lowering the poliovirus dose and possibly giving other medications with it will be crucial in its progress.

“This is a very challenging drug,” Gromeier said,” “because this is a virus that replicates, infects and kills tumor cells, and that can infect certain immune cells. We know it can work. But we have to find out how we can make it work for everybody.”

In May 2016, the FDA designated the PVS-RIPO poliovirus a “breakthrough therapy,” which allows the agency to expedite its development and review.

I heard Gromeier speak last winter at a Duke Cancer Institute event in Nags Head, N.C. I came away thinking that the PVS-RIPO poliovirus holds promise, but that Duke is many trials away from real success, if it ever achieves it. Still, there is value in promise, especially where none has existed before.

Smita Nair, a Duke immunologist who is studying the poliovirus, summarized the immunotherapy approach to cancer well in the “Breakthroughs” article:

“I think of cancer as a result of a failing immune system,” she said. “A tumor has some sort of marker on it—a protein or an antigen—that the immune system can see. [But cancer finds a way to hide.] With the poliovirus, the idea is that it will kill the cancer cells, and at the same time, it will release the tumor antigen and cause inflammation that will hopefully drive an immune response.”

Nair is currently testing the PVS-RIPO poliovirus in mice with breast cancer.

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OTHER IMMUNOTHERAPIES

Johns Hopkins is also working on driving the immune response to glioblastoma and currently has several immunotherapy drugs in phase III clinical trials, which involve hundreds of subjects, not just two dozen. By phase III, the safety and efficacy—two big hurdles—of a drug have been proved. (For a description of the four phases of clinical trials, see https://www.nlm.nih.gov/services/ctphases.html.)

Dr. Michael Lim, director of the brain tumor immunotherapy program at the Johns Hopkins Kimmel Comprehensive Cancer Center, is studying several immunotherapy drugs, known as checkpoint inhibitors, in glioblastoma. Two of these inhibitors, ipilimumab and nivolumab, have been approved by the FDA for the treatment of advanced melanoma and lung cancer.

Checkpoint inhibitors “interfere with signals from tumor cells to T cells [which are immune cells] that, in effect, direct the T cells to stand down,” according to the National Cancer Institute.

The human immune response to brain tumors is generally weak, explains Dr. Mark Gilbert, director of NCI’s Neuro-Oncology Branch, “because tumors are very effective at blunting it.” A checkpoint inhibitor seeks to boost that response.

Another challenge for immune-based glioblastoma treatments is the blood-brain barrier, which is a layer of cells that protect the brain from threats that may be circulating in the bloodstream, such as viruses. This natural barrier impedes the delivery of cancer treatments.

The NCI reports that Johns Hopkins is currently enrolling patients with recurrent glioblastoma in a phase III clinical trial designed to compare the efficacy of two checkpoint inhibitors, nivolumab and bevacizumab. Embedded in this trial reportedly will be a phase I trial (safety, dosage) testing a combination therapy of nivolumab and ipilimumab.

Dr. Lim and his colleagues also are reportedly studying whether administering localized radiation therapy to a brain tumor can not only shrink it, but kick-start an immune response that a checkpoint inhibitor or other immunotherapy could strengthen. Lim believes that such combination approaches—radiation plus immunotherapy—may offer the most promise in treating glioblastoma.

Another encouraging approach for glioblastoma is that of the therapeutic vaccine. Several are currently being studied nationwide. For more about vaccines and other immunotherapies, I refer you to the NCI summary, “With Immunotherapy, Glimmers of Progress Against Glioblastoma,” at https://www.cancer.gov/types/brain/research/immunotherapy-glioblastoma.

In my last blog, I promised a look at hereditary cancers besides BRCA-mutation cancers. I’ll turn to that subject next.

Ann, 11/24/16

 

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