Promising results that led to new $2.7 million NCI grant presented
at ASCO annual meeting on June 2
CLEVELAND – A novel gene therapy clinical trial at University Hospitals Seidman Cancer Center and the Case Comprehensive Cancer Center is showing promising results, garnering funding with a prestigious U01 Grant from the National Cancer Institute. The trial focuses on turning patients with a poor prognosis into those with a good prognosis.
This trial involves glioblastoma multiforme (GBM), the deadliest form of brain cancer and among the most difficult cancers to treat. The mean survival from the time of diagnosis is only about one year. In the trial’s Phase 1, which focuses on assessing safety rather than clinical benefit, median survival of GBM patients was 3.5-fold the expected survival based on published modeling studies with actual data from patients with similar situations in randomized clinical trials.
A $2.7 million grant to further the gene therapy study was awarded to Andrew E. Sloan, MD, Director of the Brain Tumor & Neuro-Oncology Center and the Center of Excellence for Translational Neuro-Oncology (CETNO) at UH Cleveland Medical Center and UH Seidman Cancer Center, and Stanton Gerson, MD, Director of the Case Comprehensive Cancer Center. Results of the Phase 1 clinical trial was shared on June 2 at the American Society of Clinical Oncology’s annual meeting in Chicago.
Their trial centers on the efficacy of the chemotherapeutic agents O-benzylguanine (BG) and temozolomide (TMZ) and repair enzyme MGMT, known to be an important prognostic indicator in GBM.
Since 2005, physicians have found GBM patients fall into one of two categories. Patients whose MGMT promotor is methylated and thus don’t produce much of the repair enzyme MGMT comprise the “good prognosis” group. For these patients, chemotherapy and radiation work well, and almost 50 percent of them live for two years. About 55 percent of patients, however, are unmethylated and make considerable MGMT that protects the tumor from chemotherapy. This “poor prognosis” group has a median survival of only 13.8 months.
“We began to wonder if we could convert patients from ‘poor prognosis’ to ‘good prognosis’ by inhibiting MGMT with BG,” Dr. Sloan said. “BG has two different effects: 1) It disables the tumor from repairing the damage induced by chemotherapy, and 2) By poisoning the bone marrow, the BG makes the body more sensitive to the side effects of radiation therapy.
“What if we could separate those two populations – the tumor and the bone marrow – and treat them as different compartments in the body?”
This, Dr. Sloan said, led to the idea of using gene therapy to alter MGMT.
Dr. Gerson developed a mutant gene called P140K, which does not bind to BG but repairs DNA damage caused by temozolomide. He and Dr. Sloan then took hematopoietic stem cells from patients’ blood through leukopheresis, genetically engineered them to produce P140K to make them resistant to chemotherapy, and then re-infused them into the patient to protect the bone marrow. This study is coordinated under a cooperative agreement with investigators at NCI with some patients treated there as well, Dr. Gerson said.
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