Pedro Lowenstein, M.D., Ph.D., and Maria Castro, Ph.D., are leaders in a quest to find effective treatments for brain tumors, and are in the midst of several promising research studies in various stages.

A one-two punch

Gene therapy for brain tumors gets first test in human patients

issue 23 | spring 2015

A U-M team has begun testing a unique new approach to fighting brain tumors that delivers a one-two punch designed to knock out one of the most aggressive neurological malignancies. The Phase I clinical trial of the approach, based on U-M research, delivers two different genes directly into the peritumoral region of the brain immediately following primary tumor resection.

The idea is to trigger immune activity within the brain itself to kill remaining tumor cells — the ones neurosurgeons can't resect and which lead to almost certain recurrence. It's the first time this gene therapy approach is being tried in humans, after more than a decade of research in experimental models.

A combination of therapies

One of the genes is designed to kill tumor cells directly and is activated by an oral drug, valacyclovir. The other gene spurs the body's own immune system to attack remaining cancer cells. Both are delivered into the peritumoral region via an adenovirus vector. Patients also receive the current standard of care, which includes temozolomide and radiotherapy.

The use of two vectors, Ad-hCMV-TK and Ad-hCMV-Flt3L, allows the trial to combine direct tumor cell killing (TK) and immune-mediated stimulation of anti-tumor immune responses (Flt3L).

The Phase I clinical trial has already enrolled several newly diagnosed, untreated adult patients who have tolerated the gene delivery without complications. More patients will be able to enroll at a pace of about one every three weeks, through a careful selection process. In addition to surgery and gene therapy at U-M, each will receive standard chemotherapy and radiation therapy as well as follow-up assessments for up to two years.

All patients in the study must have a presumptive diagnosis of WHO grade 3 or 4 malignant primary glioma, such as glioblastoma multiforme; patients must not have been treated yet by any therapy. They must also have a Karnovsky score greater than or equal to 70, be between the ages of 18 and 75, and not be pregnant. Other hematologic, renal and liver function criteria apply.

The objectives

The primary study objective is to determine the safety of the approach by measuring toxicity and autoimmune responses. Secondary objectives will evaluate functional status, progression-free survival and overall survival.

"We're very pleased to see our years of research lead to a clinical trial, because based on our prior work we believe this combination of cell-killing and immune-stimulating approaches holds important promise," says principal investigator Pedro Lowenstein, M.D., Ph.D., the U-M Department of Neurosurgery professor who has co-led the basic research effort to develop and test the strategy.

Co-leader Maria Castro, Ph.D., notes that the patients who agree to take part in the Phase I trial will be the first in the world to help establish the safety of the approach in humans. "Without them, and without our partners on the U-M Neurosurgery team and donors to the Phase One Foundation who support our work, we wouldn't be able to take this important step in testing this novel therapeutic approach."

In addition to surgery by Drs. Oren Sagher, Daniel Orringer, Shawn Hervey-Jumper or Jason Heth, patients will undergo 24 months of follow-up. The U-M team will keep referring physicians updated regularly on patients' progress.

Also In This Article:

Read about research the Castro/Lowenstein team has done into shutting down production of a protein that makes brain tumor cells invisible to the immune system.

Find out about Lowenstein and Castro's discovery that may contradict the currently-held concept of how brain tumors get the blood supply they need to grow, potentially altering a therapeutic model.