Immunotherapy
For Brain Cancer

How is Immunotherapy for Brain Cancer Changing the Outlook for Patients?

Reviewed by:

David A. Reardon, MD
Dana-Farber Cancer Institute

Immunotherapy for brain and nervous system cancer offers potential new treatment options for a devastating set of diseases.

Cancers of the brain and nervous system affect both adults and children, and come in several different forms. The cause of these cancers is not yet well understood. Although significant advances have been made in understanding the biology of these cancers—as well as in tumor diagnosis, treatments, and quality of life of patients with the disease—the mortality rate has remained steady for more than 30 years.

As brain tumors grow in size, they can cause a wide variety of painful and life-altering symptoms for patients with the disease, often due to the pressure these tumors inflict on the brain or the ways in which the tumors interfere with normal, healthy brain and nerve function. The majority of brain cancers are highly invasive, though this disease rarely spreads to parts of the body beyond the brain.

There are several types of brain cancer, classified by the type of cell from which they originate, including astrocytomas, gliomas, and meningiomas. Cancers of the central and peripheral nervous systems include ependymoma, neuroblastoma (which most commonly affects children ages 5 or younger), and medulloblastoma.

• Astrocytoma originates in glial cells called astrocytes, star-shaped cells involved in cell repair and nutrient transport.
• Ependymoma originates in ependymal cells lining the cerebrospinal fluid pathways.
• Glioma originates in glial cells that support and protect neurons.
• Meningioma begins in the thin membranes (called meninges) covering the brain and spinal cord.
• Medulloblastoma originates in a region at the base of the skull called the posterior fossa.
• Neuroblastoma arises in primitive nerve cells called neuroblasts that are found in an embryo or fetus.

Glioblastoma (GBM), which forms from astrocytes, is the most dangerous and aggressive form of brain cancer. GBM patients typically have short life expectancies after diagnosis. Only a quarter of newly diagnosed GBM patients survive for 24 months, and fewer than 10 percent of patients survive more than 5 years.

In the United States, brain and nervous system cancers account for 1 in every 100 cancer diagnoses, and are two of the most commonly occurring cancers in children and young adults. It is estimated that 1 in 161 individuals born today will develop brain or nervous system cancer at some point in their lives. Globally, approximately 308,000 men and women are diagnosed with cancer of the brain and nervous system every year, and more than 251,000 deaths are caused by the disease. In the United States in 2023, there will be an estimated 25,000 people diagnosed with brain and nervous system cancers, and approximately 19,000 deaths.

In children, brain cancer is the second most common form of cancer, and accounts for 26 percent of all pediatric cancers in the United States. It is the most common form of solid tumor and the leading cause of death from cancer among children.

Brain Cancer Treatment Options

Immunotherapy offers promising options for treating brain cancer, which is traditionally treated with chemotherapy, radiation therapy, and surgery.

In 2005, the chemotherapy temozolomide (Temodar®) was approved to treat newly diagnosed glioblastoma (GBM) patients based on a randomized phase III clinical study that showed that it added 2.5 months to the median survival of patients. However, over 50% of GBM tumors generate a DNA repair protein called MGMT (methylguanine methyltransferase) that effectively neutralizes temozolomide chemotherapy. These patients derive negligible therapeutic benefit from the addition of temozolomide to their treatment.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. There are currently six FDA-approved immunotherapy options for brain and nervous system cancers.

Immunomodulators

• Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced brain or nervous system cancer that has DNA mismatch repair deficiency (dMMR)
• Granulocyte-macrophage colony-stimulating factor (GM-CSF): an immunodulatory cytokine; approved in combination with naxitamab-gqgk for a subset of patients with advanced neuroblastoma
• Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced brain or nervous system cancers that have high microsatellite instability (MSI-H), DNA mismatch repair deficiency (dMMR), or high tumor mutational burden (TMB-H)

Targeted Antibodies

• Bevacizumab (Avastin®): a monoclonal antibody that targets the VEGF/VEGFR pathway and inhibits tumor blood vessel growth; approved for advanced glioblastoma
• Dinutuximab (Unituxin®): a monoclonal antibody that targets the GD2 pathway; approved for first-line treatment of high-risk pediatric neuroblastoma
• Naxitamab-gqgk (Danyelza®): a monoclonal antibody that targets the GD2 pathway; approved in combination with GM-CSF for a subset of patients with advanced neuroblastoma

Several other immunotherapies are being used to treat different types of brain cancers in clinical trials.

CRI’s Impact in Brain Cancer

Despite significant advances in the understanding of brain cancer, and improvements to diagnosis, treatments, and patient quality of life, the mortality rate for brain cancer has remained consistent for more than three decades. Support for immunology research focused on this aggressive and tragic disease is urgently needed.

• CRI has opened a phase 2 trial to test the efficacy and safety of durvalumab (MEDI4736), an anti-PD-L1 antibody being developed by MedImmune/AstraZeneca, in patients with glioblastoma (NCT02336165), with David A. Reardon, MD, Dana-Farber Cancer Institute, as principal investigator.
• Adam Williamson, PhD, a CRI postdoctoral fellow at the University of California, San Francisco, is studying how glial cells recognize and digest dead cells from a brain tumor in order to reduce the harmful inflammation that causes death of surrounding neurons.
• Bryan Choi, the recipient of a Student Training and Research in Tumor Immunology (STaRT) grant at Duke University, designed a bi-specific T cell-engaging antibody (BiTE) against the EGFRvIII tumor-specific antigen, which is expressed in a majority of glioblastoma cases, and has performed preclinical tests to determine its efficacy against EGFRvIII-expressing glioblastoma.
• With funding from a CRI Investigator Award, Alex Yee-Chen Huang, MD, PhD, at Case Western Reserve University, developed an innovative approach to tracking the activity and interactions of immune and tumor cells in real time in models of pediatric and adult brain cancers, including medulloblastoma and glioma.

New and developing brain cancer immunotherapies have the potential to reduce the harmful effects and improve survival rates for patients with brain cancer. You can explore CRI’s current research into brain cancer in our funding directory.