Clinical Trial Investigates New Gene Therapy for Brain Tumors

A clinical trial is exploring a new treatment that ultimately may help turn those with a certain type of deadly brain cancer into patients with a much better prognosis.

The phase II study, being conducted at University Hospitals Seidman Cancer Center, part of the Case Comprehensive Cancer Center, and the NIH Clinical Center in Bethesda MD recently received $2.7 million in funding from the National Cancer Institute (NCI).

The study focuses on glioblastoma multiforme (GBM), the deadliest form of brain cancer and among the most difficult cancers to treat. The median survival time from diagnosis is only about one year.

Combining Gene Therapy, Chemotherapy

In the original phase I trial, which was done to assess safety, the median survival of GBM patients was 3.5 times the expected survival time based on previous predictive studies. This led the National Institutes of Health (NIH) to fund development of a phase II study.

The study investigates the combination of gene therapy with two chemotherapy drugs: temozolomide (TMZ) and O-benzylguanine (BG), which specifically inhibits MGMT, an enzyme that allows the tumor to repair the damage TMZ inflicts on the tumor DNA. 

Since 2005, physicians have known that GBM tumors fall into one of two categories: Those that produce lots of MGMT and those that don’t.  Combining TMZ chemotherapy and radiation work in tumors that don’t produce much MGMT, and almost 50 percent of these patients live for two years after treatment. However, for the nearly two-thirds of patients who produce lots of MGMT, combination therapy produces only modest survival benefit, with median survival of 13.8 months and more complications.

Leading the study are Andrew E. Sloan, MD, Director of the Brain Tumor & Neuro-Oncology Center at UH Cleveland Medical Center and UH Seidman Cancer Center who led the original phase I study, and Stanton Gerson, MD, Director of Case Comprehensive Cancer Center, as well as colleagues at the NIH Neuro-Oncology Branch.

“We began to wonder if we could convert patients from poor prognosis to good prognosis by inhibiting MGMT with BG,” Dr. Sloan says.  However, he says, this is not so simple.

“BG has two different effects. One, it disables the tumor from repairing the damage induced by chemotherapy. Two, by poisoning the bone marrow, the BG makes the body more sensitive to the side effects of chemo and radiation therapy,” Dr. Sloan says.

The first effect explains why combining BG and  TMZ kills tumor so well; the second explains why it was so toxic to patients and why previous investigators abandoned this potent “one-two punch.” 

“This led us to wonder,” Dr. Sloan says, “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 says, led to the idea of using gene therapy to alter MGMT in the bone marrow.

Drawing on Earlier Work

Dr. Gerson previously had developed a mutant MGMT gene known as P-140K-MGMT, 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 leukapheresis, genetically engineered them to produce P-140k-MGMT to make them resistant to chemotherapy, and then re-infused them into the patient to protect the bone marrow.

They then combined TMZ and BG and found that it killed tumor as expected – but after the gene therapy, the aggressive combination seemed to be well tolerated by 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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