By Letisia Marquez | June 29, 2018
For the twelfth consecutive year, City of Hope was ranked among the nation’s very best cancer centers by U.S. News & World Report. It’s a powerful validation of our pledge to compassionate care. It’s also a reminder that the quest for a cure requires big, bold thinking – the kind of thinking behind our efforts to battle glioblastoma.
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Glioblastoma is among the deadliest of human cancers. Often, the disease comes with a devastating prognosis for patients, since current treatment options often have poor outcomes.
Now, the California Institute for Regenerative Medicine (CIRM) has awarded City of Hope $3.7 million to develop a phase 1 clinical trial for glioblastoma patients that will genetically engineer their stem cells to better tolerate chemotherapy’s side effects, allowing them to receive higher doses of the therapy.
Grant funds will be used to set up and obtain approval from the U.S. Food and Drug Administration to start the clinical trial. The project includes manufacturing of clinical-grade stem cells and improving the therapy’s effectiveness and safe use in patients. The trial is expected to start in 2019 at City of Hope and three other cancer centers.
“By genetically altering blood stem cells, we can protect them from the side effects of the chemotherapy given to glioblastoma patients, which will allow them to receive more treatments. We expect that this will lead to greater tumor-killing potential,” said John Zaia, M.D., the grant’s principal investigator, Aaron D. Miller and Edith Miller Chair in Gene Therapy and director of City of Hope’s Center for Gene Therapy.
"With fewer side effects, we are hopeful that this strategy will produce a better quality of life and improved overall survival for glioblastoma patients, who are currently faced with few treatment options.”
Surgery, followed by radiation and temozolomide chemotherapy, is the current treatment regimen for patients with glioblastoma, a type of brain cancer that has a median survival rate of approximately 15 months. Chemotherapy is associated with toxic side effects in the blood, limiting the amount of drug a patient can tolerate.
The trial will also take place at Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, Mayo Clinic Hospital in Phoenix and Case Comprehensive Cancer Center in Cleveland. In the trial, blood stem cells will be taken from glioblastoma patients prior to their receiving radiation. City of Hope’s Center for Gene Therapy will then genetically modify the cells to protect them from chemotherapy’s effects. To do this, a lentivirus would be used to infect those cells, causing them to carry the DNA that produces a mutant gene for methyl guanine methyl transferase (MGMT). It is this mutant MGMT that makes the stem cells resistant to the chemotherapy’s harmful effects, such as a low white blood cell count, needed for a patient to fight off infection. Once these stem cells are transplanted back to the patient, they should be able to tolerate the chemotherapy given for glioblastoma, hopefully improving quality of life and survival.
Two preclinical trials demonstrated that the MGMT approach was effective in treating glioblastoma.
City of Hope researchers will work closely with Hans-Peter Kiem, M.D., Ph.D., of FHCRC, as well as Lentigen Technology Inc. and Miltenyi Biotec, to set up the trial and help secure its approval. Jana Portnow, M.D., associate clinical professor with City of Hope’s Department of Medical Oncology & Therapeutics Research, will lead the clinical trial once approved.
City of Hope has made numerous strides in the treatment of glioblastoma. In October 2017, CIRM also awarded City of Hope a $12.8 million grant to conduct a phase 1 chimeric antigen receptor (CAR) T cell trial targeting an aggressive form of brain cancer — malignant glioma, which includes glioblastoma.
City of Hope is the first and only cancer center treating patients with CAR T cells targeting the IL13Rα2 antigen, a protein that is found on the cell surface of a majority of glioblastomas. It was also the first to administer CAR T therapy locally in the brain, either by direct injection to the tumor site or through infusion into the cerebrospinal fluid through the ventricular system or both.
In addition, City of Hope's Alpha Clinic, also funded by CIRM, started a clinical trial in 2015 for glioblastoma patients that used genetically modified neural stem cells — which naturally home to cancer cells — to help deliver chemotherapy to brain cancer cells.