Clinical trial targets improving tolerance of brain cancer treatment


A major obstacle to most chemotherapies is that the toxicity of the drug could significantly impair or even kill the patient.

But a Phase I clinical trial for the treatment of malignant brain tumors conducted by University Hospitals (UH) Case Medical Center, Case Western Reserve University School of Medicine and Lentigen Corporation could change that.

Researchers are using genetically engineered bone marrow stem cells, harvested from the patients themselves, to improve tolerance to chemotherapy. The process involves removing some of the patients’ own blood-forming, hematopoietic stem cells and engineering them to produce a mutant form of the MGMT gene (Methylguanine Methyltransferase) known as P140K-MGMT, before returning the cells to the patient.

They expect patients to experience less severe side effects—especially bleeding and infections—a situation that could eventually allow doctors to use higher dosages of the chemotherapy drug temozolomide and more effectively kill tumors.

The improved treatment could be a major breakthrough for the 17,000 Americans diagnosed annually with glioblastoma—one of the deadliest of all cancers. The median survival time, even with aggressive treatment, is about a year.

“We think this therapy will eventually lead to increased killing of the tumor,” says Andrew Sloan, MD, the Peter D. Cristal Chair of Neurosurgical Oncology at the school and director of the Brain Tumor and Neuro-Oncology Center at UH Case Medical Center. “But the immediate goal is to determine if patients tolerate the treatment better.”

The trial is rooted in the work of Stanton L. Gerson, MD, the Asa & Patrick Shiverick and Jane Shiverick (Tripp) Professor of Hematological Oncology and director of the Case Comprehensive Cancer Center at the university and the University Hospitals Seidman Cancer Center. His laboratory invented the mutated MGMT gene and developed its use to protect bone marrow 13 years ago.

“This a perfect example of translational research,” Sloan says. “It’s bench to bedside, from Stan’s lab more than 13 years ago to the patients today and then back to the bench. We’re learning new things every day, and hopefully a couple of years from now we’ll make it even better.”

Key to the therapy is LG631, a vector or delivery system necessary to treat the stem cells with the altered MGMT gene. It is manufactured and distributed by Lentigen and supported by an NCI STTR grant1 to Gerson. Additional funding has been provided by a grant from Ohio’s Third Frontier Commission under its Research Commercialization Program.

“We think this is a highly significant study because we’re hoping that ultimately this gene therapy can ameliorate many of the toxic effects seen by current drug therapy with temozolomide,” says Boro Dropulic, PhD, the founder, president and chief science officer of Lentigen. “If we’re able to dose-escalate, there is a huge opportunity for better outcomes for these patients.”

If the Phase I and further clinical trials prove successful, the gene therapy treatment could be generally available to patients in five to eight years.

1 Research funded by NIH grant no. R42CA128269.