Immunotherapy for Brain Cancer

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  • Brain Cancer
  • Treatment Options
  • CRI's Impact
  • Clinical Trials

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

Reviewed By: David A. Reardon, M.D.
David A. Reardon, M.D.

Brain cancer is one of the major cancer types for which new immune-based treatments are currently in development. This page features information on brain cancer and immunotherapy clinical trials for brain cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based treatments to people with brain cancer.

In the United States, brain cancer accounts for 1 in every 100 cancer diagnoses. There are several types of brain cancer, classified by the type of cell from which they originate. Gliomas, which originate in glial cells that support and protect neurons, account for about 70% of brain cancers. Astrocytomas originate in glial cells called astrocytes, the multitudinous star-shaped cells involved in cell repair and nutrient transport. Meningiomas are tumors that begin in the thin membranes (called meninges) covering the brain and spinal cord. As brain tumors grow, they can cause a wide array of challenging symptoms for patients due to pressure in the brain and/or interference with normal brain function. Most brain cancers are invasive and may crowd out healthy cells and damage normal tissue, although they rarely spread to other parts of the body.

In children, brain cancer is the second most common form of cancer, and accounts for 21% 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.

Urgent Need

It is estimated that 1 in 161 individuals born today will develop brain or nervous system cancer at some point in their lives. In the U.S., 23,770 men and women are diagnosed with cancer of the brain and nervous system every year, and 16,050 deaths are caused by the disease. Although significant advances have been made in understanding the biology of brain cancers—as well as in tumor diagnosis, treatments, and quality of life of patients with the disease—the mortality rate for brain cancer has remained steady for more than 30 years. The cause of brain tumors is not yet understood.

Glioblastoma (GBM) is the most dangerous and aggressive form of brain cancer. GBM patients typically have short life expectancies; few will live to see three years after diagnosis. For newly diagnosed GBM patients treated with current standard of care, median progression free survival is just 6.9 months, and median overall survival is 14.6 months. Only a quarter of newly diagnosed GBM patients survive for 24 months, and fewer than 10% of patients survive more than 5 years.


In 2005, the chemotherapy temozolomide (Temodar®) was approved to treat newly diagnosed 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. In 2009, bevacizumab (Avastin®) was granted accelerated approval for the treatment of GBM patients whose cancers had recurred, based on results from two phase II studies. Additionally, the targeted antibody dinutuximab (UNITUXIN®) is approved for children with neuroblastoma, a cancer of the nervous system.

CRI Contributions and Impact

Current and recent CRI-funded studies on immunotherapy for brain cancer include:

  • CRI has opened a phase II 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, M.D., Dana-Farber Cancer Institute, as principal investigator. The trial will evaluate durvalumab in three patient cohorts: patients with newly diagnosed glioblastoma who will receive durvalumab in combination with standard radiotherapy; patients who have not had bevacizumab who will receive durvalumab as monotherapy; and bevacizumab-refractory patients who will receive durvalumab in combination with bevacizumab. There will be 84 patients on this trial.
  • Adam Williamson, Ph.D., a CRI postdoctoral fellow at the University of California, San Francisco, wants to understand how brain cancer cells that have died can stick around and promote inflammation and cell death, which can cause irreversible damage. He will study how glial cells recognize and digest dead cells from a brain tumor. If he can determine how to speed up engulfment of dead tumor cells from brain tissue, it is his hope to reduce the harmful inflammation that causes death of surrounding neurons. These experiments will help spur the development of strategies to prevent brain damage after cancer treatment, thereby significantly improving survivors’ quality of life.
  • Bryan Choi, the recipient of a Student Training and Research in Tumor Immunology (STaRT) grant at Duke University, is working to develop a new strategy using Bispecific T cell Engagers (BiTEs) to treat glioblastoma. Bryan’s group has designed a 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. To date, they have shown that BiTEs are: (1) highly-specific molecules that greatly reduce the risk of toxicity; (2) have the ability to penetrate the blood-brain barrier and accumulate in intracerebral tumors; and (3) may potentially overcome multiple mechanisms of immunosuppression present in patients with glioblastoma. The information gained by his experiments have the potential to improve the clinical management of patients with glioblastoma
  • CRI predoctoral fellow Jamie Fox at the University of Pennsylvania Medical Center is studying the role of connective tissue growth factor (CTGF) in the brain cancer glioblastoma multiforme. Recent studies have shown that the miR-17~92 cluster of microRNAs—small fragments of RNA that play key roles in regulating gene expression—represses the signaling pathway of the immune molecule transforming growth factor beta (TGF-beta), which is known to be involved in tumor-induced immune evasion and which has also been shown to activate CTGF. Through her studies in laboratory models of glioblastoma multiforme, which is characterized by increased expression levels of CTGF compared to healthy brain tissue, Jamie has shown that CTGF and TGF-beta may participate in a direct feedback loop, and that miR-18a, one of six members of the miR-17~92 cluster, can interfere with this loop by acting directly on CTGF. Her next studies will focus on the functional role of CTGF overexpression or inhibition on angiogenesis and tumor growth in GBM.
  • With funding from a CRI Investigator Award, Alex Yee-Chen Huang, M.D., Ph.D., 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. Using these techniques, he hopes to identify new strategies to develop targeted immunotherapies and vaccines for brain tumors.
  • Using the intravital two-photon microscopy approach he developed to image tumor and immune cells in the brain, Dr. Huang is able to obtain images such as the one on the left, providing a snapshot of T cell responses within central nervous system (CNS) tumor microenvironment. The presence of mouse medulloblastoma tumor cells (green) in the cerebral hemisphere induces the growth of new blood vessels (yellow) in the tumor bed, accompanied by the presence of surveying T cells (red). Image courtesy of A. Petrosiute, J. Myers, K. Davis, and A. Huang, unpublished data).
  • With a grant from CRI, Sharon Gardner, M.D., at NYU Langone Medical Center is conducting a phase I study of a therapeutic vaccine composed of peptides from the tumor-specific antigens EphA2, Her2, TRP2, and gp100 mixed with the adjuvant Montanide in patients younger than 21 years of age with recurrent or refractory tumors of the central nervous system (NCT00935545). This is one of the first immunotherapy trials in the United States specifically for children with brain tumors. To date, Dr. Gardner has treated 15 patients, with no significant side effects
Featured Patient

I absolutely know that further improved quality of life, enhanced survival, and cures are already occurring, and more is on the horizon.

Jeannine Walston
Brain Cancer  |  Diagnosed 1998
Read My Story
Featured Scientist
Gavin Peter Dunn, M.D., Ph.D.
Washington University School of Medicine
CLIP Investigator  |  2016
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Brain Cancer Statistics

32 Active Clinical Trials for Brain Cancer
$400K Grant Money for Brain Cancer
15 Scientists specializing in Brain Cancer
300+ Treatments given to Brain Cancer

Clinical Trials for Brain Cancer

Current immunotherapies for brain cancer fall into six broad categories: cancer vaccines, checkpoint inhibitors, oncolytic virus therapy, adoptive cell therapy, adjuvant immunotherapies, and monoclonal antibodies. 

  • Cancer Vaccines
  • Checkpoint Inhibitors
  • Oncolytic Virus Therapies
  • Adoptive Cell Therapy
  • Adjuvant Immunotherapies
  • Monoclonal Antibodies

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Clinical studies include:

  • A phase II trial testing the HSPPC-96 vaccine in patients with recurrent glioma that can be removed with surgery (NCT01814813).
  • A phase I trial testing two adenoviral vectors, with one testing HSV1-TK, which is expected to kill brain cells and expose the tumor antigens, and one testing Flt3L, a cytokine known to cause proliferation of dendritic cells, in patients with newly diagnosed high grade glioma (NCT01811992).
  • A phase I trial testing a personalized cancer vaccine, NeoVax, in adult patients with MGMT-unmethylated, newly diagnosed glioblastoma (NCT02287428).
  • A phase I trial testing ADU-623, a vaccine targeting the EGFRvIII and NY-ESO-1 antigens, in patients with treated and recurrent grade III/IV astrocytomas (NCT01967758).
  • A phase I trial testing a dendritic cell vaccine for patients with newly diagnosed or recurrent glioblastoma (NCT02010606).
  • A pilot study to test glioma antigen peptides given along with Poly-ICLC (Hiltonol®), a Toll-like receptor 3 agonist, in pediatric patients with glioma (NCT01130077).
  • A pilot study testing glioma antigen peptides given along with imiquimod, a Toll-like receptor 7/8 agonist, in children with recurrent ependymomas (NCT01795313).
  • A pilot study testing a tumor vaccine that targets the brain tumor initiating cell (BTIC) line given along with imiquimod, a Toll-like receptor 7/8 agonist, in adult patients with grade II gliomas (NCT01678352).

A promising avenue of clinical research in brain cancer is the use of immune checkpoint inhibitors. These treatments work by targeting molecules that serve as checks and balances on immune responses. By blocking these inhibitory molecules, these treatments are designed to unleash or enhance pre-existing anti-cancer immune responses. The following trials are currently recruiting patients with brain cancer:

  • A phase III trial of nivolumab (Opdivo®), versus temozolomide (Temodar®), with radiation therapy for patients with newly-diagnosed glioblastoma (NCT02617589).
  • A phase II trial testing durvalumab (MEDI4736), an anti-PD-L1 antibody, in patients with glioblastoma (NCT02336165). This trial is sponsored by Ludwig Cancer Research in partnership with the Cancer Research Institute.
  • A phase I trial of nivolumab (Opdivo®) +/- a dendritic cell vaccine in patients with recurrent glioma, astrocytoma, or glioblastoma (NCT02529072).

Oncolytic virus therapy uses a modified virus that can cause tumor cells to self-destruct and generate a greater immune response against the cancer.

  • A phase II/III trial testing Toca 511 (vocimagene amiretrorepvec), which is based on the mouse leukemia virus and made to encode the gene cytosine deaminase, and Toca FC, an oral drug, versus the standard-of-care for patients with recurrent glioblastoma multiforme or anaplastic astrocytoma who are undergoing surgery (NCT02414165). There is also a phase I trial testing Toca 511/Toca FC combined with the standard-of-care for patients with newly diagnosed high grade glioma (NCT02598011).
  • A phase I trial testing DNX-2401 in patients with recurrent glioblastoma or gliosarcoma (NCT02197169).
  • A phase I trial testing a measles virus that produces carcinoembryonic antigen (CEA) in patients with recurrent glioblastoma multiforme (NCT00390299).
  • A phase I trial testing the herpes simplex virus HSV-1716 in pediatric patients with refractory or recurrent high grade gliomas that can be removed with surgery (NCT02031965).
  • A phase I trial testing a genetically engineered poliovirus for adult patients with recurrent glioblastoma multiforme (NCT01491893).

In this approach, immune cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response. Clinical trials include:

  • A phase I/II trial testing anti-EGFRvIII chimeric antigen receptor (CAR) T cells in patients with malignant glioma (NCT01454596).

Adjuvants are substances that boost the immune response. They can be used alone or combined with other immunotherapies.

  • A phase II trial testing Poly-ICLC (Hiltonol®), a Toll-like receptor 3 agonist, in patients with recurrent pediatric grade I or II astrocytoma (NCT01188096).
  • A phase I/II trial testing indoximod, an IDO inhibitor, in patients with recurrent glioma (NCT02052648).
  • A phase I trial of indoximod and temozolomide (Temodar®) for pediatric patients with brain cancer (NCT02502708).

Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.

  • A phase II trial of ABT-414, an antibody-drug conjugate (ADC) that targets EGFR/EGFRvIII, in patients with newly diagnosed glioblastoma (NCT02573324).
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Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Cancer Facts & Figures 2016; Cedars Sinai Brain Tumors and Brain Cancer web page; GLOBOCAN 2012; CRI grantee progress reports and other CRI grantee documents

Updated March 2016

*Immunotherapy results may vary from patient to patient.