Cancer Immunotherapy

Brain Cancer

Brain cancer is one of the major cancer types for which new immune-based cancer 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 cancer treatments to people with brain cancer.

In the United States, brain cancers account for 1 in every 100 cancer diagnoses. Gliomas, which originate in glial cells, the cells that support and protect neurons, account for about 70% of brain cancers. Astrocytoma tumors originate in glial cells called astrocytes, the multitudinous star-shaped cells involved in cell repair and nutrient transport, whereas meningiomas are tumors that begin in the thin membranes covering the brain and spinal cord called meninges. 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 27% of all pediatric cancers in the United States. It is the most common form of solid tumors 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., 23,380 men and women are diagnosed with cancer of the brain and nervous system every year, and 14,320 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-term 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 under 10% of patients survive more than 5 years.

Current Treatments

In 2005, 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 open label, phase II studies. Although 26% of patients who received bevacizumab had partial responses, most lasted less than six months and there was no evidence of improvement in overall survival.

Immunotherapies in Development

Some immunotherapies that have shown promise in improving survival and have moved into late-phase clinical trials include:

  • Rindopepimut (CDX-110), a therapeutic vaccine targeting a mutant peptide called EGFRvIII, that is expressed in approximately one-third of GBM tumors. Rindopepimut is currently being tested in the following trials that are enrolling patients with EGFRvIII positive tumors: a phase III trial in patients with newly diagnosed glioblastoma (NCT01480479) and a phase II trial in patients with relapsed glioblastoma (NCT01498328). For information on the 3 phase II trials of rindopepimut that formed the basis for the current randomized phase III trial, see Celldex’s recent news release summarizing the results.
  • DCVax-L, a dendritic cell vaccine derived from a patient-specific tumor lysate, in a phase III trial to treat newly diagnosed glioma (including glioblastoma/glioblastoma multiforme and astrocytoma) that is currently enrolling patients. (NCT00045968)
  • ICT-107, a dendritic cell vaccine utilizing synthetic peptides against tumor associated antigens commonly expressed by GBM tumors and GBM stem cells. A randomized phase II clinical trial has been completed and encouraging preliminary results of patient benefit have been reported (see recent news release by ImmunoCellular Therapeutics). (NCT01280552)
  • Nivolumab and Ipilimumab, are anti-PD-1 and anti-CTLA-4 antibodies, respectively, that are currently being produced by Bristol-Myers Squibb, and are in a phase II clinical trial for recurrent glioblastoma. (NCT02017717)
  • HSPPC-96 is a vaccine approach that is currently in a phase II trial in patients with recurrent glioma that can be removed with surgery.  (NCT01814813)
  • Anti-EGFRvIII chimeric antigen receptor (CAR) T cells is a cancer treatment to collect white blood cells from a patient, modify them to act against the EGFRvIII protein, and returning them to the body in a phase I/II clinical trial against malignant glioma. (NCT01454596)
  • Indoximod, an IDO inhibitor, is in phase I/II trial for recurrent glioma. (NCT02052648)
  • ADU-623 is a vaccine expressing the EGFRvIII-NY-ESO-1 antigens in a phase I trial in patients with treated and recurrent grade III/IV astrocytomas. (NCT01967758)
  • AMG 595, an antibody-drug conjugate (ADC) composed of an agent targeting EGFRvIII with the chemotherapy mertansine (DM1), in a phase I trial enrolling patients with recurrent gliomas (NCT01475006)
  • ABT-414, is an antibody-drug conjugate (ADC) that targets EGFR/EGFRvIII and is in a phase I trial that is currently enrolling newly diagnosed GBM patients. (NCT01800695)

CRI Contributions and Impact

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

  • 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 by generating a novel therapeutic.
  • 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.


Sources: National Cancer Institute; National Cancer Institute Physician Data Query (PDQ); American Cancer Society Cancer Facts & Figures 2014; Cedars Sinai Brain Tumors and Brain Cancer web page; GLOBOCAN 2012; CRI grantee progress reports and other CRI grantee documents

Last Updated June 2014


Brain Cancer News & Stories

Reviewed By:

David A. Reardon, M.D.
David A. Reardon, M.D.
Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute

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