How Immunotherapy Can Treat Multiple Neurologic Conditions

How Immunotherapy Can Treat Multiple Neurologic Conditions
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​Manipulating the immune system can help treat many conditions, including multiple sclerosis, myasthenia gravis, and certain types of epilepsy. Learn how it works.

​The immune system is the body's natural line of defense against disease. When a foreign invader—such as a virus, bacteria, or microbe—attacks the body, immune cells recognize the threat and rush to surround and destroy it.

Illustration by Jeannie Phan

​But sometimes, this internal army doesn't do its job properly. In the case of autoimmune diseases such as multiple sclerosis (MS), the immune system gets its wires crossed, seeing normal, healthy cells as a threat and attacking them, says David Hafler, MD, FAAN, endowed professor of immunobiology at Yale School of Medicine in New Haven, CT. In other cases, such as with certain cancers, the disease itself develops ways to fool the immune system into perceiving it as harmless and allowing it to grow.

"Immunotherapy is a broad term that covers many treatments that target the immune system in order to help it do its job more effectively," says Dr. Hafler. There are two main types of immunotherapies: modulation and activation.
Immune ModulationImmune modulation therapies put the brakes on overactive or misdirected immune system activities, helping to control autoimmune conditions such as MS and myasthenia gravis (MG).

MULTIPLE SCLEROSIS. In MS, specific cells in the immune system known as macrophages (Latin for "big eaters") are directed by T cells and attack the central nervous system, causing inflammation and destruction of a substance called myelin, which protects the nerve fibers in the brain, spinal cord, and optic nerves. This damage interferes with the communication between the brain and the rest of the body, says Robert J. Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. (For more about MS, visit BrainLifeMag.org/Basics-MS and BrainLifeMag.org/MS.)

The first immune-modulating drugs to be approved by the US Food and Drug Administration (FDA) for MS were interferon-beta 1b (Betaseron) in 1993 and interferon-beta-1a (Avonex) in 1996, which are both synthetic versions of a natural protein that the immune system makes to combat viruses, Dr. Fox explains.

"We now have more than a dozen immune-modulating therapies that slow disease progression, each with a different mechanism of action in the immune system," he says. "For example, natalizumab (Tysabri) is an antibody that blocks white blood cells from adhering to the blood vessel wall so they cannot cross the blood-brain barrier and get into the brain to cause inflammation."

Dr. Hafler was among the first researchers to demonstrate that myelin-reactive T cells (which play a central role in the immune system) are different in MS patients than in healthy controls, which strongly suggests that MS is an autoimmune disease. He says that ocrelizumab (Ocrevus), the most recently approved drug for MS, represents a new frontier. "For years, MS research has focused primarily on T cells, but more recently we have learned that B cells appear to be the primary vehicle to turn on the T cells. To partially deplete them in the circulation, as ocrelizumab does, has dramatic effects on the disease."

Ocrelizumab is the only drug approved for patients with the primary progressive form of the disease, in which neurologic function worsens from the start of symptoms without relapses or remission. It is also approved for patients with the relapsing-remitting form of MS for which all other MS drugs have been approved. "When we've applied most immune therapies to progressive MS, they've almost always failed," says Dr. Fox. He notes that ocrelizumab may have succeeded because the trial on which its approval was based included a significant number of young patients with active inflammation. "We suspect that progressive MS has different components that are probably neurodegenerative and will require either a different type of immune-modulating therapy, or some sort of neuroprotective treatment."

Another limitation of immune therapy for MS is the inability to tailor treatments for the specific patient. "All of our treatments for MS work to different levels of effectiveness across big populations of patients, but we haven't gotten smart enough to figure out how to match the right therapy to the right patient other than through the process of elimination," Dr. Fox says.

MYASTHENIA GRAVIS. In MG, the immune system attacks certain receptors in the muscles that receive nerve impulses, short-circuiting messages from the nerves telling the muscles to contract and causing weakness in muscles that control the eyes, face, neck, and limbs. A hallmark of MG is that muscle weakness worsens with activity and improves after periods of rest, explains Nicholas Silvestri, MD, associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences in New York. "There is a lot of variability to the disease. It can fluctuate significantly even day by day, but it tends to be most aggressive around the time of diagnosis before treatment starts. It also can flare up when there are other infections of the body or because of stress."

Most patients with MG are treated with immunosuppressive drugs to restore full function and to improve quality of life. "Initially, most people are controlled with steroids like prednisone, but because of the many long-term side effects, those are used only in the short term," Dr. Silvestri explains. Longer-term immunosuppressant treatment involves a range of drugs that include azathioprine (Imuran), mycophenolate mofetil (CellCept), and cyclosporine, a generic drug available under different brand names. "It was once thought that immunosuppressant treatment needed to be lifelong, but recent research suggests that if you've been stable for a few years, it may be possible to taper down to a very low dose. But that still requires further research."

If symptoms become severe—for example, if the person cannot open his eyes or move his lips—a blood product taken from human donors, called immunoglobulin, may be given through an intravenous infusion. Known as IVIG, this therapy temporarily modifies the immune response with the normal antibodies from the donated blood; a 2014 review published in the journal Expert Review of Clinical Immunology found good evidence for the use of IVIG in patients whose MG was worsening or who were in "myasthenic crisis," a complication in which the muscles that support breathing and swallowing become so weak that the person requires mechanical help to breathe. IVIG therapy can be used along with other treatments or until regular medications begin working.

"Some people are on IVIG all the time for MG," says Dr. Silvestri. "Some centers like that and some don't. It's an accepted treatment, although for convenience's sake it's probably not ideal to be on infusion therapy all the time."
EPILEPSY. Some patients with epilepsy who do not respond to anti-seizure drugs may have autoimmune epilepsy. In autoimmune epilepsy, seizures are triggered by antibodies that attack proteins in the brain, and while patients may not respond fully to standard anti-epileptic drugs, they may respond to immunotherapies such as IVIG. A 2016 study published in PLOS One found that more than 75 percent of patients with autoimmune epilepsy improved with immunotherapy, and more than half were seizure free by four weeks after the initial treatment.

And for a certain type of seizure, known as faciobrachial dystonic seizures, which are characterized by frequent, brief, rapid involuntary muscle movements of the face and arm on the same side, recent research shows that patients should begin immunotherapy as soon as possible to prevent long-term cognitive impairment. A 2018 review published in Brain in February found that seizures stopped within 30 days in more than 50 percent of patients with faciobrachial dystonic seizures who were treated with immunotherapy, including IVIG and azathioprine. Eighty-eight percent were free from seizures within three months. For every day that immunotherapy was delayed after diagnosis, the probability of stopping the seizures declined.

Immune ActivationImmune activation therapies either kick the immune system into overdrive or attack a target, such as cancer cells.

Among these immunotherapies are monoclonal antibodies, which are man-made versions of immune system proteins that can be designed to attack a specific part of a cell; immune checkpoint inhibitors (drugs that block certain proteins that keep the immune system in check); and vaccines, injected to initiate an immune response, says Howard Colman, MD, PhD, director of medical neuro-oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

GLIOBLASTOMA. Immunotherapy has had some significant successes in cancer treatment over the past several years.

Unfortunately, it has been less successful in treating primary brain tumors such as glioblastoma, at least so far. "Many of the approaches that have had significant success in subsets of disease in other solid tumors have been less effective, or not effective at all, in glioblastoma," says Dr. Colman.

A vaccine called rindopepimut, designed to target a particular mutation found in more than a quarter of all glioblastomas, showed promise in early trials. But in 2017, a large phase 3 trial found that when used with standard chemotherapy, the vaccine did not improve survival rates compared with standard treatment. "While the study found that the vaccine was successful in activating the immune system against that mutant protein, there was no effect on outcomes," Dr. Colman says. "Other studies are assessing checkpoint inhibitor drugs, but so far these have not shown any significant difference in overall survival either. We still hope that in certain situations, if we are able to understand more about how the immune system functions in the brain, we might be able to design immunotherapy that is more effective in glioblastoma."

Other checkpoint inhibitors-including drugs targeting TIGIT, an immune receptor present on some T-cells—may work more effectively in brain tumors, says Dr. Hafler. "In 2015, our group published a study in Neurology suggesting that TIGIT may be a checkpoint inhibitor for tumor evasion in the central nervous system, and within a year we hope to launch a trial of an agent targeting TIGIT in glioblastoma."

CAR-T cell therapy, in which a patient's own immune cells are harvested and re-engineered in the laboratory to attack cancer cells, is also being studied in glioblastoma. A case report published in the New England Journal of Medicine in December 2016 described a 50-year-old man with an aggressive glioblastoma that had spread to his spinal fluid; his tumor regressed significantly in response to CAR-T therapy. "But other patients in that trial, and patients in other trials of CAR-T therapy targeting different antigens, haven't done as well," says Dr. Colman. "As with many types of treatment, using immunotherapy to target brain tumors is much more complicated than cancers of the lung, kidney, or other organs."

OTHER NEUROLOGIC CONDITIONS. Novel immunotherapy drugs are being studied in other neurologic diseases, such as Parkinson's and Alzheimer's disease, but the research is very preliminary, says Dr. Hafler. "I was a naysayer on an autoimmune component to Parkinson's disease, but recent research has shown good evidence that an abnormal immune reaction may contribute to this disease." This includes a 2017 study published in Nature, in which T-cells in blood samples from Parkinson's patients showed an immune response to proteins found in neurons—a response not seen in healthy controls. Three drugs are now in development for Parkinson's disease, but it's too early for results. In some phase 1 trials, monoclonal antibodies have been found to reduce the amyloid plaques characteristic of Alzheimer's disease, but those and other immunotherapy approaches are also still in the very early stages." For now, immune activation therapies, like those approved for some cancers, are not available for any neurologic conditions outside of a clinical trial.

The Risks Of ImmunotherapyTreatments designed to jump-start the immune system, slow it down, or direct its activities all come with risks. Each immune therapy has its own specific list of side effects, but here is an overview of some of the most common ones.

Risk: Jipangan from the Noun ProjectIMMUNE ACTIVATION THERAPIES. Because they block the body's natural safeguards against immune overactivation, immunotherapies can cause side effects that are similar to autoimmune reactions. Common ones include skin rashes; diarrhea, abdominal pain, and other gastrointestinal symptoms; problems with liver or thyroid function; sudden onset of diabetes; lung inflammation; and inflammatory arthritis, according to a review published in the Journal for ImmunoTherapy for Cancer in 2017. Less common side effects include cardiac symptoms, blood and kidney abnormalities, and neurologic symptoms such as encephalitis (inflammation in the brain). Patients receiving immunotherapy also sometimes experience infusion reactions during or shortly after treatment, including fever, tightness in the chest, wheezing and shortness of breath, irregular heart rate, and drops in blood pressure. These are usually mild, but in some cases they can be severe and even life-threatening.

IMMUNE MODULATION THERAPIES. Many of the disease-modifying drugs for MS share a range of similar potential side effects. Depending on the therapy, these can include flu-like symptoms; gastrointestinal problems such as nausea and diarrhea; headache; fatigue; rash; and, for injectables, reactions at the injection site, says Robert J. Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. Less common but more serious risks, depending on the drug, include infusion reactions; cardiac, kidney, and liver toxicity; blood disorders; susceptibility to infections; increased risk of malignancies; and, in the case of certain drugs, a serious brain infection known as progressive multifocal leukoencephalopathy.

IMMUNOSUPPRESSANTS. Immunosuppressant drugs, such as those taken to treat MG, increase susceptibility to infection. People taking these drugs must take precautions to avoid exposure to infectious diseases. Other side effects include nausea, vomiting, diarrhea, loss of appetite, insomnia, mood changes, weight gain, fluid retention, increased susceptibility to diabetes, high blood pressure, osteoporosis, glaucoma, cataracts, and stomach ulcers, says Nicholas Silvestri, MD, associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences in New York.

INTRAVENOUS IMMUNOGLOBULIN (IVIG). Side effects such as headaches and mild allergic reactions can be alleviated by slowing the rate of infusion, says Dr. Silvestri. Other side effects include flushing, chills, muscle pain, wheezing, rapid heart rate, nausea, and drops in blood pressure. In rare cases, more serious adverse events have occurred, including blood clots and stroke, meningitis, kidney failure, and severe allergic reactions.

Full Disclosure
The experts interviewed for this article have the following disclosures to report.

David Hafler, MD, FAAN, endowed professor of neurology and immunobiology at Yale School of Medicine, has been a paid consultant for Novartis Pharmaceuticals, EMD Serono, BMS, Sanofi, and Med Immune.

Robert J. Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, receives consulting fees from several companies that either sell or are developing therapies for multiple sclerosis, including Actelion, Biogen, EMD Serono, Genentech, Novartis, and Teva.

Nicholas Silvestri, MD, associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences in New York, has consulted for Alexion, which makes eculizumab, a drug used to treat myasthenia gravis.
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Howard Colman, MD, PhD, director of medical neuro-oncology at the Huntsman Cancer Institute at the University of Utah in Salt Lake City, is a member of the advisory board or a consultant for several pharmaceutical companies, including AbbVie, Merck, DNATrix, and BeiGene, among others.

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