Glioblastoma: genes + chemistry
Scientists are testing a new method of gene therapy for glioblastoma
Scientists are developing a way to treat glioblastoma multiforme using gene therapy, – writes eurekalert.org (Cleveland researchers test novel gene therapy for glioblastoma).
Researchers at the University Hospital in Cleveland, the Seidman Cancer Center and the Case Comprehensive Cancer Center have made some progress in developing a treatment for glioblastoma.
The study examines glioblastoma multiforme (MGB) – the most difficult to treat and the most deadly form of brain cancer. The average life expectancy from the moment of diagnosis is only about one year. In phase 1 of the study, which focuses on safety assessment rather than clinical benefit, the median survival of patients with MGB was 3.5 times higher than expected survival based on published model studies with evidence from patients with similar situations in randomized clinical trials.
Andrew Sloan, MD, Director of the Center for Brain Tumors and Neurooncology and the Center of Excellence in Translational Neurooncology (CETNO) at the Cleveland and California Medical Center, received a grant of $2.7 million to continue research in the field of gene therapy in collaboration with the Seidman Cancer Center and Stanton Gerzon, MD, Director comprehensive Cancer Center Case. The results of the first phase of the clinical trial were presented on June 2 at the annual meeting of the American Society of Clinical Oncology in Chicago.
The studies were based on the effectiveness of the chemotherapeutic agents O-benzylguanine (BG) and temozolomide (TMZ) and the reparative enzyme MGMT, which is an important prognostic indicator in MGB.
Since 2005, doctors have found that patients with MGB fall into one of two categories. Patients in whom the promoter of the MGMT gene is methylated and, therefore, does not produce most of the MGMT reparative enzyme make up the "good prognosis" group. For these patients, chemotherapy and radiation therapy work well, and almost 50 percent of them live for two years. Approximately 55 percent of patients, however, have an unmethylated promoter that produces a significant amount of MGMT, which protects the tumor from chemotherapy. In this group with a "poor prognosis", the median survival is only 13.8 months.
"We started wondering if we could move patients from a 'bad prognosis' to a 'good prognosis' by suppressing MGMT with BG," Dr. Sloan said. – BG has two different effects: 1) it does not allow the tumor to repair the damage caused by chemotherapy, and 2) poisoning the bone marrow, BG makes the body more sensitive to the side effects of radiation therapy."
The desire of scientists to separate these two populations – tumor and bone marrow – and treat them as different parts of the body" led to the idea of using gene therapy to change MGMT.
Dr. Gerson has 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 using leukopheresis, genetically engineered them to produce P140K to make them resistant to chemotherapy, and then injected them back into the patient to protect the bone marrow.
Gene therapy, in particular, was carried out using a new lentiviral vector with modified safety, similar to those used for CAR T-cell therapy. The results to date have been promising.
"Stan Gerson has been working on MGMT for 30 years and is a world expert," says Dr. Sloan. "It turns out that MGB is the only cancer where it really matters!"
The study was conducted with very few side effects among patients. All eligible patients underwent at least one cycle of progressively increasing dose of chemotherapy with five cycles of increasing dose of BG and TMZ as the median. Median survival was 3.5 times longer than expected, and the MGMT mutant was 3-26 times higher in peripheral blood than in patients who were not treated with this treatment.
"This regimen was tolerable, safe and allowed for an increased dose of chemotherapy with an impressive improvement in survival compared to a large set of studies selected for comparison," said Dr. Sloan.
Drs. Sloan and Gerson are also considering the best sequence of surgeries, radiation, chemotherapy and reinfusion of genetically engineered stem cells. Phase I of the trial tested three possible sequences. It is noteworthy that three out of five patients in one of the three groups not only survived three years, but also did not have a relapse of the disease after this period of time. Five out of 10 patients in the study lived more than four times longer than expected.
At the next stage, which will open before the end of the year, according to Dr. Sloan, the team plans to study the interaction with the immune system and find out how and why the tumor recurs in some patients.
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