I came across this article explaining all the various therapies (defined by category) now available for GBM.
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 23% 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.
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., 22,850 men and women are diagnosed with cancer of the brain and nervous system every year, and 15,320 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 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. 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.
IMMUNOTHERAPY 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 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:
- Rindopepimut (Rintega®, CDX-110) is a therapeutic vaccine targeting a mutant peptide called EGFRvIII, which is expressed in approximately one-third of glioblastoma tumors. The FDA granted rindopepimut a Breakthrough Therapy Designation—which expedites the process for getting FDA approval—for patients with EGFRvIII-positive glioblastoma, based on a randomized, placebo-controlled phase II trial (ReACT) indicating that rindopepimut has a survival benefit among recurrent patients. An international phase III trial of rindopepimut in newly diagnosed glioblastoma completed its enrollment in December 2014 and is no longer accruing (NCT01480479).
- A randomized, placebo-controlled phase III trial testing DCVax-L, a dendritic cell vaccine derived from a patient’s own tumor, for newly diagnosed glioma (including glioblastoma/glioblastoma multiforme and astrocytoma) (NCT00045968).
- A randomized, placebo-controlled phase IIb trial studying ICT-107, a dendritic cell vaccine that targets six different antigens associated with glioblastoma multiforme, in patients with newly diagnosed glioblastoma following resection and chemoradiation (NCT01280552; this study is ongoing, but not recruiting participants).
- A phase II trial testing the HSPPC-96 vaccine in patients with recurrent glioma that can be removed with surgery (NCT01814813).
- A phase II trial testing ERC1671, a cancer vaccine composed of a combination of glioblastoma tumor cells, in patients with recurrent or progressive, bevacizumab-naïve glioblastoma multiforme or gliosarcoma (NCT01903330).
- A phase I/II trial testing SL-701, a vaccine comprised of multiple synthetic peptides, in adult patients with glioblastoma multiforme in first recurrence (NCT02078648).
- A phase I trial testing ICT-121, a dendritic cell vaccine pulsed with CD133, which is expressed on glioblastoma and glial stem cells, in patients with recurrent glioblastoma multiforme (NCT02049489).
- 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 dendritic cell vaccine administered with imiquimod, a Toll-like receptor 7/8 agonist, in adult and pediatric patients with glioma (NCT01808820) and pediatric patients with brain cancer (NCT01902771).
- A phase I trial testing a tumor vaccine given with the adjuvant Montanide (ISA 51) in adult patients with newly diagnosed glioblastoma (NCT01702792).
- A phase I trial testing a tumor vaccine that targets the brain tumor initiating cell (BTIC) line, GBM-6, given along with imiquimod, a Toll-like receptor 7/8 agonist, in pediatric patients with diffuse intrinsic pontine glioma (NCT01400672).
- 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 phase I trial testing a cytomegalovirus vaccine given along with basiliximab (Simulect®), an antibody that targets an immune-suppressing molecule in tumors, in patients with newly diagnosed glioblastoma multiforme (NCT00626483).
- 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 pilot study testing a dendritic cell vaccine in patients with newly diagnosed glioblastoma (NCT01957956).
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 testing Opdivo® (nivolumab) and Yervoy® (ipilimumab)—anti-PD-1 and anti-CTLA-4 antibodies, respectively—in patients with recurrent glioblastoma (NCT02017717).
- A phase II trial testing MEDI4736 (durvalumab), 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 II trial testing Keytruda® (pembrolizumab), an anti-PD-1 antibody, with or without Avastin® (bevacizumab), in patients with recurrent glioblastoma multiforme (NCT02337491).
Oncolytic Virus Therapies
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 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 Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector that expresses the cytosine deaminase gene, in adult patients undergoing surgery for grade III or IV gliomas (NCT01985256).
- 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).
Adoptive Cell Therapy
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).
- A phase I trial testing anti-EGFRvIII chimeric antigen receptor (CAR) T cells in patients with glioblastoma (NCT02209376).
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).
Monoclonal antibodies are molecules, generated in the lab, that target specific antigens on tumors.
- A phase I/II trial testing TRC105, an anti-endoglin antibody, in patients with recurrent glioblastoma multiforme (NCT01648348).
- A phase I trial testing ABT-414, an antibody-drug conjugate (ADC) that targets EGFR/EGFRvIII, in patients with newly diagnosed glioblastoma (NCT01800695).