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The Impact of Immunotherapy on the Brain

Chemotherapy is a blunt instrument: It kills cancer, along with everything else in its wake. Immunotherapy, conversely, has a laserlike focus and can specifically target diseased cells. The immunotherapeutic approach focuses on educating and equipping the patient’s own body to fight disease while sparing healthy cells and reducing the risk of treatment.

For Omar Al-Louzi, MD, a neurologist and director of the Cedars-Sinai Visual Outcomes Laboratory, and John Yu, MD, director of Surgical Neuro-Oncology and vice chair of neurosurgical oncology in the Department of Neurosurgery, immunotherapy treatments present a unique opportunity to fight aggressive diseases with dire prognoses like brain cancer, Alzheimer’s disease and Parkinson’s disease. 

Dendritic Cell Vaccines as Glioblastoma Treatment

Yu and his colleagues were among the first to identify a cancer stem cell that initiates and propagates tumors in glioblastoma, the most common and aggressive form of brain cancer. A small population of the cancer stem cells that drive the growth of these tumors is resistant to both chemo and radiation therapies, and the median survival period of patients with glioblastoma is 14 months.

Novel therapies are needed to address this devastating disease. Immunotherapies, such as dendritic cell vaccines that teach the immune system to recognize and target brain tumors or damaged tissue, present a unique opportunity to provide effective treatment with milder side effects compared to chemotherapy and radiation therapy.

“Most drugs used for cancers are chemotherapies, which are like napalm. They destroy whatever they see, and they work by preventing the growth of cells,” said Yu. “They will kill cancer cells, but they will also kill your blood cells, make your hair fall out and weaken your intestines. The advantage to immunotherapy is its ability to focus on a certain diseased cell type.”

One method of immunotherapy being explored in a new clinical trial involves removing a portion of white blood cells from the patient through leukapheresis and separating them into T-cells and dendritic cells. The dendritic cells are then manipulated and activated to present antigens to the T-cells and then “teach” the T-cells which proteins to target.

The T-cells are then activated, expanded to create a sort of army that can recognize abnormal proteins on the cancer stem cells, and put back into the bloodstream. Dr. Yu hopes that, by traveling through the patient’s circulatory system, the T-cells will find the brain tumor and attack it, leaving the rest of the cells and tissue intact.

This research builds on a previously successful multi-institutional trial in which dendritic cells were injected directly under the skin so they would migrate to the lymph nodes and teach the T-cells already in the body to attack the cancer. Results indicated that patients lived without recurrence about two months longer after undergoing this therapy. When considering a prognosis of 12-14 months, that is a 20% increase in survival. With the new trial, Yu and his team hope to continue to increase survival time. 

The Ability of Antibodies to Slow or Reverse Neurodegenerative Disease

Al-Louzi has also seen significant progress in the development of immunotherapies that may help to slow—or potentially reverse—consequences of conditions that involve significant neurodegeneration. There have been especially meaningful advances in Alzheimer’s disease research over the past four years.

In Alzheimer’s, aggregates of proteins outside of cells fold abnormally, leading to amyloid plaques, or plaques of proteins that are aggregated and toxic. Similarly, within nerve cells, abnormal proteins called tau can occur that can be toxic to the neuron.

Immunotherapies that use antibodies to target both the toxic tau proteins and amyloid plaques are being developed and trialed in the hope of treating the disease. One such therapy uses an antibody known as aducanumab, which is designed to target amyloid plaques and reduce their numbers.

“Initial clinical trial results failed to show slowing in the decline of certain basic functions related to cognitive behavior in patients,” said Al-Louzi. “However, when that data was aggregated across clinical trials and studied in specific patient populations, there were actually signs that cognitive decline was slowing. Our hope is that by reducing the burden of those misfolded proteins through immunotherapies, we can achieve significant clinical improvement in well-selected patient populations.”

There are additional ongoing randomized clinical trials testing other forms of therapies against amyloid plaques and tau proteins. Al-Louzi is optimistic the next few years will bring more options to support Alzheimer’s patients.

“Now we are studying the effect of antibodies on reducing amyloid burden on the retina and the brain,” said Al-Louzi. “Through positron emission tomography and innovative retinal imaging, we can get a picture of the back of the eye and actually see the accumulation of amyloid plaques in Alzheimer’s patients, sometimes even when they are not yet symptomatic or fall into the mild cognitive impairment category. Our goal is to see if we can get the antibodies to reach both the brain and retinal amyloid plaques.”

Vaccines as Future Neurodegenerative Treatment

Immunotherapies can also be leveraged to treat other neurodegenerative diseases, such as Parkinson’s disease and multiple system atrophy, which are caused by aggregations of a different type of abnormal substance called alpha-synuclein. Newer studies are expanding beyond antibodies to include vaccination as a potential immunotherapy delivery system.

“Some studies have looked at alpha-synuclein vaccines as a way of mitigating cell-to-cell transfer of the proteins that accumulate in Parkinson’s disease,” said Al-Louzi. “Most have been preclinical studies in mice, but results have been promising. If we can find a safe and successful way to apply this therapy to humans, it could increase novel treatment approaches for these conditions.”

Additional research is focused on determining if vaccination against amyloid plaques or tau proteins generates a similar response.

“The field is in a state of evolution at the moment,” said Al-Louzi. “Vaccination could be another front to help fight neurodegeneration in the human nervous system.”