Immunotherapies for glioblastomas
Mayo Clinic in Rochester, Minnesota, is enrolling patients in clinical trials of immunotherapies for glioblastomas. Separate trials are testing novel treatments for patients with newly diagnosed tumors and patients with recurring disease.
Glioblastomas are the most common primary brain tumors affecting adults, and few patients survive five years after diagnosis. Therapeutic vaccines, which combine tumor antigens with dendritic cells created from patient monocytes, are an effort to boost the patient's immune system to eliminate the tumor. The clinical trials reflect advances in obtaining tumor antigens and in culturing dendritic cells.
"We are making huge strides at a basic-science level that can be translated to patients," says Ian F. Parney, M.D., Ph.D., a consultant in the Department of Neurologic Surgery at Mayo Clinic in Rochester, Minnesota, who is leading the clinical trials. "We understand much more about these tumors and about how we can stimulate the immune system to eradicate them."
Trial for newly diagnosed tumors
Previous versions of therapeutic vaccines have typically required samples of a patient's tumor to provide antigens. The supply of antigens from an individual patient's tumor sample is limited, yet fresh antigens are needed to make vaccine for long-term therapy.
The Mayo Clinic trial for newly diagnosed glioblastomas takes a different approach. Dr. Parney and Allan B. Dietz, Ph.D., co-director of the Mayo Clinic Human Cellular Therapy Laboratory, have created a library of clinical-grade brain-tumor cell lines from patients, eliminating reliance upon tumor samples from individual patients. As with previous versions of glioblastoma vaccines, dendritic cells will be cultured from individual patients' white blood cells.
"Proteins from the tumors will be expressed in the context of the patient's own molecules. From that point of view, treatment is individualized," Dr. Parney says. "But we aren't required to get fresh tumor for any given patient, and we can make much more vaccine to give to each patient."
Manufacture of the trial vaccine, which is done at a good manufacturing practices-approved facility at Mayo Clinic, incorporates improved techniques for culturing dendritic cells. Successful vaccine treatment requires mature dendritic cells; immature dendritic cells work to suppress the immune system. But standard methods for culturing dendritic cells — which were developed using healthy donors' white blood cells — generate a higher number of immature dendritic cells when applied to white blood cells from glioblastoma patients.
"With the Human Cellular Therapy Lab, we've developed a technique that allows us to generate large numbers of mature dendritic cells from the monocytes of brain tumor patients," Dr. Parney says. "We think this is a much more potent way of making dendritic cells."
Analysis of the laboratory's glioblastoma cell lines pinpointed antigens commonly present in brain tumors, and allowed for the development of tests for specific antigen responses. "That is something which we've never been able to do previously in trials," Dr. Parney notes. "From as little as 5 milliliters of whole blood, we can test 120 different markers on the surface of white blood cells. We get a very detailed picture of the immune system in the peripheral blood of any individual patient."
Preliminary data from an earlier study suggest it may be possible before treatment to differentiate patients who might respond to immunotherapy. "Replicating that finding will help us tailor treatment going forward," Dr. Parney says. "At some point, if we can identify groups of patients who aren't going to respond to vaccine, we might be able to alter their immune systems to achieve response."
The development over the next few months of a similar trial for patients with recurrent glioblastomas "looks very promising," Dr. Parney says. In the meantime, Mayo Clinic is participating in a multicenter study, through the Alliance for Clinical Trials in Oncology, of heat shock protein peptide complex treatment for recurrent glioblastomas.
Heat shock proteins chaperone other proteins into the immune system. The clinical trial uses vaccine made from heat shock protein peptide complexes extracted from individual patients' tumor samples. Patients must undergo surgery to remove all visible tumor to provide antigens for their vaccines.
Trial participants are randomized into one of three groups:
- One receiving bevacizumab (Avastin) alone
- One receiving the medication plus vaccine
- One receiving the vaccine alone
Patients in the third group may be prescribed medication if their tumors progress.
Mayo Clinic is also investigating nonvaccine methods — notably, immune checkpoint inhibitors — to modulate the immune systems of glioblastoma patients. Ipilimumab (Yervoy), used to treat melanoma, blocks the immune-suppressing CTLA-4 receptor, and may be used in clinical trials for glioblastoma. Other work focuses on the PD-L1 checkpoint.
"Ultimately, we may arrive at a point where we combine immune-modulation treatment and the vaccine," Dr. Parney says. "Although we have made great progress, we have a ways to go to really optimize immunotherapy for brain tumors. Right now, we're kind of at the Model T version. We want to get a Ferrari."
For more information
Alliance for Clinical Trials in Oncology. Vaccine therapy with bevacizumab versus bevacizumab alone in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. ClinicalTrials.gov.
Mayo Clinic. Vaccine therapy and temozolomide in treating patients with newly diagnosed glioblastoma. ClinicalTrials.gov.