Is Immunotherapy the Key to Treating Brain Cancer?

While progress in brain tumor treatment has been slow, new research has the brain cancer community buzzing. Recent work contributing to an understanding of the molecular mechanisms and gene mutations, combined with clinical trials, is leading to more promising and tailored therapeutic approaches.

Immunotherapy is a new modality showing potential in patients who receive a diagnosis of glioblastoma multiforme (GBM)—the most common and most aggressive brain cancer with a strong resistance to conventional therapies and a high relapse rate. In 2014, the American Cancer Society estimates about 23,000 new cases of brain and other nervous system tumors will be diagnosed and that there will be more than 14,000 deaths from these tumors.

Immunotherapy can include treatment with monoclonal antibodies, cancer vaccines and other therapies that stimulate an immune response to help the body recognize and attack cancer cells—all with the goal of ultimately shrinking tumors and prolonging lives.

Monoclonal antibodies are synthetic immune system proteins and are quite prolific in cancer treatment now. The monoclonal antibody Avastin (bevacizumab) has been used to treat recurrent or resistant brain cancer since it was approved by the Food and Drug Administration in 2009.

Different forms of immunotherapy already have led to major improvements in the outcomes of some cancers, including resistant HER2-positive breast cancer, lymphomas, leukemias and melanoma. However, malignancies of the brain represent more of an enigma to researchers, resulting in slower adoption of immunotherapies than in other cancers.

While many vaccines are used to prevent diseases, vaccine therapy as a cancer treatment is gaining speed. Provenge (sipuleucel-T), the first cancer therapeutic vaccine, which uses the patient’s own immune dendritic white cells that are “boosted” against a prostate cancer specific antigen, was approved in 2010 to treat advanced prostate cancer. Since then, there has been an abundance of cancer vaccine clinical trials, but no new vaccine has been approved.

“The first thing that a brain cancer has to do in order to grow and be successful to survive and thrive in its human host is to make itself invisible,” says Keith L. Black, chair of the department of neurosurgery at Cedars-Sinai Medical Center in Los Angeles. Secondly, brain cancer works to weaken or suppress the immune system. “It’s a strategy that cancers employ, particularly brain cancer.”

A diversity of cells constitutes a brain tumor, posing additional challenges. Also, “the central nervous system is cordoned by the blood-brain barrier that limits the access of common therapeutic agents,” says Nabil Ahmed, a pediatric oncologist at Texas Children’s Cancer and Hematology Centers in Houston. “Modern immunotherapy has been able to overcome this limitation with some success.” But more potent and personalized agents requiring advanced technology are needed to propel further progress.

It’s a different form of therapy. What we’re trying to do with the brain is not to replace the standard of care, but to add another category of treatment.

Typical treatment for GBM begins with surgery to extract malignant tissue from the brain, followed by radiation and chemotherapy to kill lingering cancer cells. In many cases, the cancer reappears several months later. For a select number of patients, this could lead to another operation and possibly more chemotherapy. Now, there is hope that the inclusion of immunotherapy along with this regimen can have a positive influence.

“It takes time to develop that immune response,” says Donald M. O’Rourke, an associate professor of neurosurgery at the University of Pennsylvania’s Abramson Cancer Center and the Perelman School of Medicine in Philadelphia. “The more rational goal of immunotherapy is to prevent a recurrence rather than reduce what’s already there. It’s a different form of therapy. What we’re trying to do with the brain is not to replace the standard of care, but to add another category of treatment.”

Because there is significant variation among GBMs and the patients that have them, one-size-fits-all treatments cannot address their needs. A number of personalized immunotherapy treatments in brain cancer are currently being tested. Among them, the DCVax-L vaccine for newly diagnosed GBM, which is created by combining dendritic cells (the patient’s own immune cells) and the patient’s own tumor tissue in the laboratory. Now that the dendritic cells can “identify” the patient’s cancer cells, they are injected back into the patient and alert the immune system to attack those specific cells.

“In our previous clinical trials of immunotherapy for GBM, there appears to be an interesting tail end of survivors—10 years or more,” says Linda M. Liau, principal investigator of the DCVax-L trials and director of the Brain Tumor Program at the Ronald Reagan University of California, Los Angeles Medical Center. In a phase 1/2 study, a third of patients have lived a median of at least four years or more. Traditionally, fewer than 10 percent of GBM patients receiving standard care survive five years or more. The vaccine is currently being tested in a phase 3 study. Patients must enter screening at a participating site before surgery to treat the tumor.

Another phase 3 study is investigating the efficacy and safety of a combination of the chemotherapy Temodar (temozolomide) and the investigational drug rindopepimut—a cancer vaccine that could promote anti-tumor effects in newly diagnosed patients whose GBM tumors express the EGFRvIII protein, a byproduct of a mutation seen in about a third of GBM cases.

Also factoring in the individuality of patients’ tumors, the Prophage Series vaccines, including the Prophage G-200 series, which is undergoing phase 2 clinical trials—are tailored uniquely to each person’s cancer. Like DCVax-L, every vaccine is manufactured using the surgically removed tumor. However, instead of using the patient’s own dendritic cells, the Prophage vaccines contain the heat shock protein gp96. This protein is used in the vaccine because it carries around tumor-specific peptides extracted from the tumor tissue. Once injected, the patient’s immune system would be able to identify the heat shock protein gp96 and peptides complex, giving the immune system a way to identify the cancer cells and attack them.

Results of the phase 2 study have shown it improves survival in patients with recurrent GBM. The results, published in Neuro-Oncology earlier this year, showed that patients who received the vaccine after surgery had a median survival of more than 10 months. Comparatively, patients who have a recurrence of their brain tumor historically have a median survival of about 3 to 6 months. The vaccine had few side effects, but mostly included fatigue and skin sensitivity to the injection.

Because the phase 2 study did not include a control group, scientists are unable to confirm if the vaccine is better than Avastin, often used for recurrent GBM. Another phase 2 study is underway to compare the vaccine with Avastin. The trial will look at how the vaccine, given either in combination with Avastin or followed by Avastin at disease progression, compares to the regimen of Avastin alone.

ICT-107 is another approach that uses a patient’s dendritic cells to harness the immune response. “The goal is for the ICT-107 vaccine to stimulate the patient’s immune response to kill the remaining brain tumor cells after surgery and chemotherapy,” says Texas Children’s Ahmed.

The vaccine is being studied after surgery in patients with newly diagnosed GBM in combination with standard treatment of radiation and chemotherapy. Disappointing data showed no improvement in survival, but it did delay progression of the disease. Further results may be available this summer at the annual meeting of the American Society of Clinical Oncology.

Unlike traditional chemotherapy and radiation, all of these brain cancer vaccines theoretically target only malignant cells and do not harm healthy cells. This means that these vaccines are particularly gentle, with limited toxicities.

As the scientific community gains a better understanding of the diversity of brain tumor cells and the ways in which they evade the host immune system, immune-based therapies will likely become part of the antitumor options used to treat these deadly cancers.

As the scientific community gains a better understanding of the diversity of brain tumor cells and the ways in which they evade the host immune system, immune-based therapies will likely become part of the antitumor options used to treat these deadly cancers.