In Brain Tumor Therapeutics, Options for Bypassing the Blood-Brain Barrier Are Burgeoning

For brain tumor researchers, the blood-brain barrier is a barrier in more ways than one: Not only does it prevent most therapeutics — particularly anticancer agents — from reaching the brain, but it also has been the dominant barrier to significant progress in treating primary brain tumors.

“Of the very few tools we have to treat primary brain tumors — surgery, radiation therapy and tumor-treating fields — most don’t require direct bloodstream access to the brain,” says Cleveland Clinic neurosurgeon Michael A. Vogelbaum, MD, PhD. The remaining tools, he adds, are a limited number of chemotherapies, and the most effective of those, temozolomide, crosses the blood-brain barrier at only about 40 percent of its systemic concentration.

“This is why we have made very little progress in treating primary brain tumors for decades now,” notes Dr. Vogelbaum, who serves as Associate Director of Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center.

Delivering drugs directly to the brain

Impatience with the challenges posed by the blood-brain barrier has prompted Dr. Vogelbaum and his Cleveland Clinic colleagues to develop what is likely the nation’s broadest offering of clinical trials of therapies designed to deliver medications directly to the brain to treat primary brain tumors.

“The general strategy of direct therapeutic delivery to the brain was validated more than two decades ago with the approval of Gliadel® Wafers for brain tumor treatment,” explains Dr. Vogelbaum. “While that therapy is no longer in widespread use, it demonstrated the benefit of delivery directly to brain tissue, and a number of attempts are underway to build on that via a variety of approaches.”

Those approaches fall into several categories:

• Injecting a therapeutic directly into the brain during brain tumor resection
• Slow delivery of a therapeutic into the brain over hours or days via a convection-enhanced delivery (CED) or cannula device
• Delivery of a therapeutic to the brain through the spinal fluid

Dr. Vogelbaum notes that delivery via spinal fluid has been difficult and disappointing in the setting of primary brain tumors, but the other two categories of direct delivery have shown promise in various stages of human testing. “These approaches are gaining traction, and Cleveland Clinic has developed broad and deep expertise in this area,” he says. To illustrate, he outlined a number of ongoing clinical trials in which Cleveland Clinic is participating.

Direct injection in the Toca 5 Trial

This multicenter phase 2/3 study is evaluating direct injection of the viral vector Toca 511 into the tumor resection cavity of patients undergoing surgical resection for recurrent high-grade glioma. This experimental agent is designed to infect tumor cells and make them more sensitive to Toca FC, an extended-release formulation of flucytosine that is given orally starting several weeks after resection. Patients are being randomized in open-label fashion to either this experimental treatment or standard of care (resection followed by lomustine, temozolomide or bevacizumab).

Target enrollment is 380 patients. Cleveland Clinic was one of the initial three enrolling sites. “The fact that this therapy has reached phase 3 studies is quite promising for a brain tumor therapeutic,” Dr. Vogelbaum says.

Convection-enhanced delivery of the targeted toxin MDNA55

The rest of the ongoing direct delivery trials involve administration via CED or cannula devices, each from a different manufacturer. The first is a single-arm phase 2 study of MDNA55, a fusion protein comprising a genetically engineered interleukin-4 that’s linked to a modified form of the potent cell-killing compound Pseudomonas aeruginosa exotoxin A. “This targeted toxin couldn’t be administered any other way than by direct delivery,” says Dr. Vogelbaum. “If given systemically, it would irreversibly damage the liver.”

The study population is adults with recurrent or progressive glioblastoma; target enrollment is 52 patients. Cleveland Clinic is one of approximately 10 participating centers.

Cannula delivery of the oncolytic adenovirus DNX-2401

DNX-2401 is an oncolytic adenovirus designed to cause brain tumor cells to destroy themselves. It’s delivered intratumorally with use of a reflux-resistant cannula and is being studied in combination with the immune checkpoint inhibitor pembrolizumab in a single-arm phase 2 trial known as CAPTIVE. Cleveland Clinic is one of about a dozen centers participating in the study, which aims to enroll 48 adults with recurrent glioblastoma or gliosarcoma.

Convection-enhanced delivery of topotecan

Cleveland Clinic is conducting a single-center pilot study of the delivery of the chemotherapy agent topotecan to tumor-infiltrated brain via the Cleveland Multiport Catheter (CMC), a four-port CED device developed at Cleveland Clinic by a team led by Dr. Vogelbaum. The illustration at the top of this post shows the infusion of a tumor using the CMC.

The study aims to enroll 18 patients with recurrent high-grade glioma. As Dr. Vogelbaum reported at a November 2017 meeting of the Society for Neuro-Oncology (see details here), results from the trial’s first 12 patients show that the CMC conveys high volumes of topotecan to both enhancing and nonenhancing tumor regions.

The company that is commercializing the CMC is now exploring using the device to deliver other brain tumor therapies in additional clinical trials.

A focus on treatment monitoring

Dr. Vogelbaum notes that in all of these studies, Cleveland Clinic researchers are focusing on the delivery of treatment to the brain tissue as well as on monitoring the penetration of therapies and the biological effects they are having. “We co-infuse gadolinium or other tracers to observe exactly where the injected therapy is going — and where it isn’t reaching,” he says. “We do this in our own CED trials, and we are one of only two centers that did this early in the clinical development of Toca 511.”

He adds that his team’s monitoring of treatment effects is crucial to accelerating progress. “If we look at treated tumor tissue and find that it’s not being impacted biologically, we can either modify the treatment early in the course of development or abandon it,” he says. “This is the type of flexible and broad approach that’s needed if we are to make long-overdue treatment progress against primary brain tumors. Cleveland Clinic is excited to be offering such a wide range of options to patients interested in direct therapeutic delivery.”

Dr. Vogelbaum is one of the inventors of the Cleveland Multiport Catheter (CMC) and leads the Cleveland Clinic team testing the device. He is founder and chief medical officer of Infuseon Therapeutics Inc., a Cleveland Clinic-owned spinoff company that is funding clinical development of the CMC. His roles in this development effort are covered under a Cleveland Clinic-approved conflict-of-interest management plan.