With Immunotherapy, Glimmers of Progress against Glioblastoma

Glioblastoma cells in culture. Researchers hope that immunotherapies will improve outcomes in patients with this aggressive brain cancer.

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Treatment advances for patients with glioblastoma, an aggressive form of brain cancer, have been uncommon. But latest studies have raised hopes that immunotherapy, which has recently established itself as a proven therapy for several types of cancer, may be able to switch sides this trend.

Patients diagnosed with glioblastoma, the most common malignant brain tumor in adults, typically sustain fewer than fifteen months after diagnosis. Despite continued efforts to develop and test fresh therapies for glioblastoma, none have improved survival appreciably.

However, in early-stage clinical trials, several different immunotherapies have shown promise against glioblastoma, including some that have produced long-lasting responses in patients with advanced disease. And now at least three immunotherapies are in phase III clinical trials, the results of which may form the basis for Food and Drug Administration (FDA) approvals.

But just because a therapy looks promising in early-stage trials does not mean that it will succeed in larger randomized trials. Even so, researchers who specialize in brain cancer are genuinely, if cautiously, optimistic about immunotherapy`s prospects.

«Just the fact that we have some phase III trials in glioblastoma, where for years we had a hard time getting past phase II trials, is an encouraging sign,» said Michael Lim, M.D., who directs the brain tumor immunotherapy program at the Johns Hopkins Kimmel Comprehensive Cancer Center. «So, for the very first time in a long time, there`s some real excitement.»

Cracking Down Barriers

When it comes to the brain, immune-based treatments face some substantial obstacles before they can even reach a tumor.

The most significant challenge is the blood–brain barrier, a layer of tightly packed, specialized endothelial cells that form the blood vessels in the brain and contractile cells called pericytes. While this barrier protects the brain from threats that may be circulating in the bloodstream, like viruses or toxins, it can also impede the delivery cancer treatments.

In addition, the immune response to brain tumors is generally feeble, «because tumors are very effective at blunting it,» explained Mark Gilbert, M.D., director of NCI`s Neuro-Oncology Branch.

Nevertheless, studies have now shown that the immune system has sentries that can react to foreign threats in the brain and that immune cells from other parts of the assets can travel there, Dr. Gilbert continued, «albeit the mechanisms that permit that to happen aren`t very clear.»

These are formidable obstacles for immune-based treatments to overcome in treating brain cancers, acknowledged John Sampson, M.D., Ph.D., chair of the Department of Neurosurgery at Duke University Medical Center and director of Duke`s Brain Tumor Immunotherapy Program.

«But I don`t think they limit most of the immunotherapy approaches being studied,» he said.

Therapeutic Vaccines on Board

Among the immunotherapies being studied for the treatment of glioblastoma are several therapeutic vaccines, including a so-called peptide vaccine, rindopepimut. The central component of rindopepimut is a fragment, or peptide, of a mutated form of the epidermal growth factor receptor (EGFR) protein called EGFRvIII.

Approximately twenty to thirty percent of patients with glioblastoma have tumors that express EGFRvIII. Because EGFRvIII is voiced almost exclusively by glioblastoma cells and is not found on healthy brain cells, it is an attractive target around which to develop immune-based treatments, explained Dr. Sampson, who primarily developed rindopepimut.

Initial findings from a puny randomized trial of rindopepimut demonstrated an improvement in both median overall survival and 6-month progression-free survival in glioblastoma patients who received the vaccine and bevacziumab (Avastin®) compared with patients who received a placebo vaccine.

According to longer-term data, at two years of follow-up, twenty five percent of patients treated with rindopepimut were still alive, compared with no patients in the control arm. These findings were reported in November two thousand fifteen at the Society for Neuro-Oncology annual meeting by the trial’s lead investigator, David Reardon, M.D., of the Dana-Farber Cancer Institute.

The vaccine`s manufacturer, Celldex Therapeutics, has finished enrollment in a phase III trial testing rindopepimut in patients with freshly diagnosed EGFRvIII-positive glioblastoma who have undergone surgery to have their tumors eliminated. [UPDATE: On March 7, 2016, Celldex announced that it was halting this phase III trial. The decision was based on findings from an interim data analysis which showcased that patients receiving rindopepimut were unlikely to have an improvement in overall survival compared with patients in the control arm.]

Vaccines composed primarily of immune cells known as dendritic cells are also being studied as potential therapies for glioblastoma.

Because dendritic cells primarily orchestrate immune responses, they are often called the generals of the immune system, Dr. Lim explained. «So it makes sense to use the general,» he said.

These vaccines are typically patient specific. Their production entails a sophisticated manufacturing process that involves collecting immature immune cells from each patient, coaxing them to develop into dendritic cells, and engineering them to produce a tumor-specific immune response when they`re administered back to the patient.

One of the dendritic cell vaccines that is furthest along in testing for glioblastoma is DCVax-L®. In a petite phase I/II trial testing DCVax-L in patients with operable glioblastoma, the median survival was approximately thirty one months. Northwest Biotherapeutics, which manufactures the vaccine, is presently enrolling patients with operable, freshly diagnosed glioblastoma in a phase III trial.

Dr. Sampson`s team at Duke has developed a dendritic cell vaccine that is engineered to target cells that express proteins, or antigens, induced by infection with cytomegalovirus (CMV)–a very common virus that up to eighty percent of adults aged forty and older have been infected with. For reasons that are still unclear, glioblastoma cells, but not healthy brain cells, tend to express these CMV antigens, Dr. Sampson said.

Earlier this year, the researchers reported promising results from a 12-patient clinical trial of the vaccine. Patients who received the dendritic cell vaccine in combination with the tetanus and diphtheria (Td) vaccine–given to further strengthen the immune response–had a median survival of more than three years, compared with approximately eighteen months in patients who received the dendritic cell vaccine alone.

Much of the data from the vaccine trials that have been conducted to date are preliminary and need to be replicated in larger randomized trials, Dr. Sampson acknowledged.

But they are all pointing in the right direction, he continued. «There`s clearly something going on here, and I`m encouraged by it.»

Supercharged T Cells

Another type of immune-based treatment, called CAR T-cell therapy, is also being tested against glioblastoma. This treatment–which, like some of the vaccines being tested, typically requires engineering cells collected from patients and then returning them to the patient–has already demonstrated success in early-stage clinical trials in patients with advanced cancers, including melanoma and leukemia.

Researchers from NCI`s Center for Cancer Research and several large cancer centers have launched trials testing CAR T-cell therapy in patients with glioblastoma.

At the Baylor College of Medicine, investigators have developed «bi-specific» CAR T cells. The therapy relies on T cells collected from the patient that have a strong affinity for CMV-infected cells. And, because approximately eighty percent of glioblastoma cells overexpress a receptor that trusses to the HER2 protein (perhaps best known for its role in breast cancer), the T cells are also engineered to express a receptor that ties to HER2.

This treatment is very much in the early testing stages. In November 2015, at the Society for Immunotherapy of Cancer annual meeting, Nabil Ahmed, M.D., of Baylor reported preliminary findings from a petite trial testing bi-specific CAR T cells in pediatric and adult patients with advanced glioblastoma. Only one patient experienced enough tumor shrinkage to qualify as a partial response (at least thirty percent reduction in tumor size), but five patients have had a stabilization in their disease that has lasted for more than ten weeks.

«From a scientific standpoint and from a creativity standpoint, CAR T cells are a very interesting treatment for glioblastoma,» Dr. Gilbert said.

These early trials should help reaction significant questions, he added, including «how well the T cells are tracking to tumors.»

Checkpoint Inhibitors Check In

Several immunotherapy drugs known as checkpoint inhibitors are also advancing to late-stage clinical trials in patients with glioblastoma. Checkpoint inhibitors interfere with signals from tumor cells to T cells that, in effect, direct the T cells to stand down.

Two checkpoint inhibitors, ipilimumab (Yervoy®) and nivolumab (Opdivo®), have been approved by the FDA for the treatment of advanced melanoma and lung cancer, and promising results have been reported for these and other drugs in this class in several other cancer types.

There`s solid evidence to support testing checkpoint inhibitors against glioblastoma, Dr. Lim explained. In some patients with advanced melanoma, treatment with ipilimumab, which targets the CTLA-4 checkpoint protein on T cells, has shrunk brain metastases. And in some animal model studies, checkpoint inhibitors have eradicated glioblastoma tumors.

A phase III clinical trial comparing nivolumab, which targets the checkpoint protein PD-1, against bevacizumab in patients with glioblastoma that has returned after prior treatment is presently enrolling patients. Embedded within this trial is a phase I trial testing nivolumab in combination with ipilimumab.

The Neuro-Oncology Branch has launched an early-stage trial that is testing PD-1 and CTLA-4 inhibitors, either alone or in combination, along with the chemotherapy drug temozolomide, in patients with freshly diagnosed glioblastoma. Because of slight differences in how these two therapies work, Dr. Gilbert explained, there may be a benefit to combining the treatments.

Eventually, he said, a large trial testing them alone and in combination will be needed to determine their optimal use in patients with glioblastoma.

Dr. Lim and his colleagues, meantime, are studying whether administering localized radiation therapy to a brain tumor can not only help shrink it, but also kick commence an immune response that could be strengthened further by a checkpoint inhibitor or other immunotherapy–a response referred to as the «abscopal effect.»

Based in part on findings from a recently published animal model examine, they are launching an early-phase trial testing this treatment treatment in patients with advanced melanoma that has spread to the brain.

Ultimately, Dr. Lim believes, combination approaches, consisting of either immune-based therapies or immune and traditional therapies, may suggest the most promise.

«We need to keep studying our options and find the best combinations that are the most effective and least toxic for our patients,» he said.

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