Despite aggressive treatment with surgery, radiation, and chemotherapy, glioblastoma typically recurs within a few months and causes death within 2 years. In hopes of prolonging the survival of patients with newly diagnosed or recurrent glioblastoma, researchers at The University of Texas MD Anderson Cancer Center are investigating immunotherapy approaches such as immune checkpoint inhibitors, modified T cells, cord blood–derived natural killer (NK) cells, and STAT3 (signal transducer and activator of transcription 3) inhibitors.
“We see about 300 new patients with glioblastoma every year,” said John de Groot, M.D., a professor in and chair ad interim of the Department of Neuro-Oncology. “And we have some exciting immunotherapy studies for these patients.”
Challenges and opportunities
Glioblastoma has several characteristics that impede clinicians and researchers. “Some tumors, such as lung cancer or melanoma, have high mutational loads, which result in a long list of antigens that can be targeted for treatment. But this is not the case for glioblastoma,” said Amy Heimberger, M.D., a professor in the Department of Neurosurgery. On a scale of the number of mutations within various types of cancer, Dr. Heimberger said, glioblastoma falls in the middle range.
Along with a limited number of mutations, tumor heterogeneity is a hallmark of glioblastoma. Thus, there are few targets, and the same targets do not occur in all patients. “Because these tumors are heterogeneous, one drug is not going to be a home run that cures most patients,” Dr. Heimberger said.
Finally, the blood-brain barrier presents a challenge to glioblastoma treatment and was once believed to prevent immune cells in the bloodstream from reaching the brain. However, research at MD Anderson and elsewhere has shown that such immune cells do indeed reach brain tumors, making immunotherapy an option. “It’s been shown that inflammation in the brain can open up the blood-brain barrier so that immune cells can gain access to the brain parenchyma,” said Tomasz Zal, Ph.D., an associate professor in the Department of Immunology.
Dr. Zal’s laboratory is one of the first in the world to use two-photon microscopy, which enables researchers to visualize fluorescently stained cells deep in living tissue. Dr. Zal and his colleagues use this technology to study tumor formation and the immune response in the brains of living mice.
“Understanding the mechanisms of the immune response can help us schedule immunotherapy doses,” Dr. Zal said. “Timing is critical in immunotherapy: all is dependent on when immune cells are recruited to the tumor.” He added that close collaboration between MD Anderson clinicians and basic scientists enables them to explore multiple approaches to immunotherapy.
When possible, clinicians like to begin a patient’s immunotherapy regimen as soon as glioblastoma is identified—and before resection. When immunotherapy is administered during this “window of opportunity” in clinical trials, the treatment’s effects are studied in the surgical specimen at the time of resection.
“These window-of-opportunity trials allow us to give an immunotherapy and determine whether a sufficient number of immune cells are trafficking to the tumor and whether those immune cells are functionally able to kill the cancer,” Dr. Heimberger said. “These trials are starting to reveal secrets of the tumor microenvironment and may help us identify strategies that could further enhance the immune response.” The window-of-opportunity concept is exploited in two trials that are currently enrolling patients with glioblastoma at MD Anderson: one in which patients receive an immune checkpoint inhibitor and another in which patients receive autologous modified T cells.
“In one of the most promising trials in our immunotherapy portfolio, patients with recurrent glioblastoma are given a checkpoint inhibitor before surgery,” Dr. de Groot said. In this clinical trial (No. 2014-0820), patients receive two doses of the PD-1 (programmed cell death protein 1) inhibitor pembrolizumab before surgery. The patients continue to receive the drug after surgery until disease progression or unacceptable toxic effects occur.
Dr. Heimberger, a co–principal investigator of the trial along with Dr. de Groot, said, “I think there will be a subset of patients in this trial who respond to monotherapy with an immune checkpoint inhibitor, but it is likely that a combination of immune therapeutics that enhance immune targets, immune activation, and immune cells’ trafficking to tumors will work best for our future patients.”
Adoptive T cell therapy
Another ongoing trial (No. 2014-0899) uses autologous cytomegalovirus-specific T cells. “Almost everyone experiences cytomegalovirus infection in their lifetime, and there’s a possible association between the virus and glioblastoma,” Dr. Heimberger said. She added that while it is not clear whether cytomegalovirus has a role in glioblastoma formation, cytomegalovirus-specific antigens such as CMV pp65 are known to be expressed in glioblastoma.
Research led by Elizabeth Shpall, M.D., and Katy Rezvani, M.D., Ph.D., both professors in the Department of Stem Cell Transplantation and Cellular Therapy, showed that cytomegalovirus-specific T cells can home to the tumor tissue but that a large proportion of the T cells’ effector function is suppressed. The researchers then developed a strategy to rapidly expand polyfunctional, highly cytotoxic virus-specific T cells. Such T cells are used in the current trial.
The trial, led by Marta Penas-Prado, M.D., an assistant professor in the Department of Neuro-Oncology, has two treatment arms in its phase II portion: one in which patients with recurrent glioblastoma begin T cell therapy before surgery and one in which patients with newly diagnosed glioblastoma begin T cell therapy after surgery and radiation therapy. In both treatment arms, patients’ T cells are removed by leukapheresis. Each patient’s T cells are cultured with CMV pp65 and expanded in MD Anderson’s Good Manufacturing Practice and Cellular Therapy Facility, which is led by Drs. Shpall and Rezvani.
After leukapheresis, patients in both treatment arms receive dose-dense temozolomide for the first 21 days of the 42-day cycle. On day 22, the patients receive their first infusion of autologous cytomegalovirus-specific T cells. For the patients with recurrent glioblastoma, resection is performed on day 30. Patients in both treatment arms continue receiving dose-dense temozolomide and T cell infusions for a total of four 42-day cycles followed by standard-dose temozolomide monotherapy until disease progression or unacceptable toxic effects.
“Temozolomide is the standard of care, and if you time it just right—give the chemotherapy and then the immunotherapy—you get an expansion of the immune response,” Dr. Heimberger said. Similar to the pembrolizumab trial, analysis of the tumors resected after treatment with temozolomide and modified T cells will help Dr. Heimberger and her colleagues to quantify the extent of that immune response and ascertain whether the immune response corresponds to treatment response.
Allogeneic NK cells from umbilical cord blood are an attractive immunotherapy option for several reasons. First, NK cells, unlike T cells, do not require a specific antigen for activation. Second, allogeneic NK cells can produce a graft-versus-tumor effect without causing graft-versus-host disease. Also, cord blood NK cells can be stored as an off-the-shelf treatment, and their safety has been demonstrated in clinical trials for patients with myeloma, lymphoma, and leukemia.
Before researchers could design a clinical trial of cord blood–derived NK cells in patients with glioblastoma, they needed to know whether glioblastoma patients’ own NK cells trafficked to the tumors. Drs. Rezvani and Heimberger studied NK cells in specimens from resected glioblastomas and found that NK cells reach tumors but become dysfunctional in the tumor microenvironment.
Dr. Rezvani and her group performed in vitro studies to find the reason for NK cell dysfunction. “When we cultured healthy cord blood NK cells with glioblastoma cells together, the NK cells were active at first,” Dr. Rezvani said. “But after a while the glioblastoma cells induced dysfunction in the NK cells, and this dysfunction was mediated through tumor growth factor [TGF]-β.” Further, the researchers found that blocking prevented glioblastoma-induced NK cell dysfunction.
As a result of these findings, a clinical trial of cord blood NK cells combined with a TGF-β inhibitor for glioblastoma patients is expected to open later this year. Dr. Penas-Prado will be the principal investigator. The NK cells for the trial will be expanded in the Good Manufacturing Practice and Cellular Therapy Facility from cord blood units provided by MD Anderson’s cord blood bank, which is led by Dr. Shpall.
In another trial expected to open soon, patients with glioblastoma will receive WP1066, a STAT3 inhibitor developed at MD Anderson by Waldemar Priebe, Ph.D., a professor in the Department of Experimental Therapeutics. “This drug can get past the blood-brain barrier and has activity against the cancer itself as well as immunological activity,” said Dr. Heimberger, the trial’s principal investigator. “Almost all mechanisms of tumor-mediated immune suppression tie into STAT3.”
In addition to the immunotherapy trials specifically for patients with brain tumors, patients with glioblastoma often are eligible to receive new immunotherapy agents in clinical trials that are open to patients with any type of solid tumor through the Department of Investigational Cancer Therapeutics. “These trials that are open to patients with all sorts of tumors are a nice opportunity for our patients,” Dr. de Groot said. “And sometimes results from those trials will lead us down an avenue to develop an agent specifically for patients with glioblastoma.”
Dr. de Groot and his colleagues are hopeful that their research will clarify the role of immunotherapy in the multimodal treatment of glioblastoma and ultimately extend survival for their patients.
For more information, call Dr. John de Groot at 713-745-3072, Dr. Amy Heimberger at 713-563-8717, Dr. Katy Rezvani at 713-794-4260, or Dr. Tomasz Zal at 713-563-3252.
OncoLog, March 2017, Volume 62, Issue 3