BioPharma

Why is glioblastoma such a tough nut to crack?

Almost no new therapies have succeeded in extending patient survival in GBM in the last 20 years, and the field is littered with drugs that have failed despite promising early data. But researchers soldier on with new molecular targets and therapeutic modalities.

Human brain is made of multi-colored wooden blocks. Creative medical or business concept.

However often people refer to “cancer” in the singular, it’s more accurate to see it as a spectrum of diseases, akin to the great multitudes of autoimmune disorders, infectious diseases or neurological conditions, all with their own prognoses and treatments. That might make it easier to understand why some cancers are relatively easy to cure, others incurable but more like chronic diseases and others still invariably and rapidly fatal.

A member of that third group of cancers is the brain cancer glioblastoma multiforme, or GBM for short, the one that ended the lives of Sens. John McCain and Ted Kennedy and former Vice President Joe Biden’s son, Beau. But since Percival Bailey and Harvey Cushing coined the cancer’s name in 1926, it remains today one of the toughest of all: incurable, with a current median overall survival of less than two years.

The latest letdowns came in just the last few months. In September, San Diego-based Tocagen announced that its Phase III study of the gene therapy and prodrug combination Toca 511 and Toca FC in recurrent GBM had failed to show an improvement in overall survival, and in fact showed that patients in the study group did worse than those in the control group. The Tocagen news, which sent the company’s stock tumbling 80% and resulted in large-scale layoffs, came a week after Bristol-Myers Squibb said that the Phase III CheckMate-548 trial of Opdivo (nivolumab) failed to meet its primary endpoint, as previous trials of the drug in GBM already had done. became only the latest study of that drug in GBM to fail.

The last drug to improve overall survival in GBM – and then by only a couple of months – was Merck oral chemotherapy agent Temodar (temozolomide), which received Food and Drug Administration approval for frontline GBM in 2005 and is now available in generic form. The only other therapy to improve survival in recent years is a device, Novocure’s Optune, which has been available since 2011. Roche’s Avastin (bevacizumab) received full FDA approval for recurrent GBM in 2017. But that was after it spent years in regulatory limbo, with a 2009 accelerated approval based on its ability to prevent progression of GBM by starving tumors of blood, despite never having shown an improvement on the gold-standard endpoint of overall survival – meaning the amount of time patients are actually alive.

“I think it highlights the fact that glioblastoma is a very difficult tumor to treat,” said Dr. Michael Lim, a neuro-oncologist at Johns Hopkins University, in a phone interview. “The blood-brain barrier has proven to be a big issue, so getting drugs into the tumor might be more challenging.”

In the U.S., the standard of care in first-line treatment of GBM typically consists of surgical resection of the tumor followed by temozolomide and radiation, while Avastin is used after recurrence, often in conjunction with an investigational therapy given in a clinical trial.

In a 2018 paper in the journal Neuro-oncology, Mayo Clinic neuro-oncologist Dr. Jann Sarkaria and others wrote that accumulation in GBM tumors of radiographic contrast material that normally does not penetrate the blood-brain barrier has led to the widespread belief that the barrier is uniformly disrupted in the disease. But they presented evidence to support their hypothesis that all patients with GBM have regions of their tumor that contains an intact blood-brain barrier, and curing the cancer will only become possible if those regions are adequately treated.

“The necrotic parts of the tumor are generally leaky, so they’re generally accessible,” said Dr. Floris Barthel, a post-doctoral researcher at The Jackson Laboratory in Farmington, Connecticut, whose research focuses on cancer genomics, in a phone interview. “It’s about getting the drug into the diffuse parts of the brain where the tumor cells are hiding.”

But the blood-brain barrier is only one of several factors that have thwarted efforts to develop drugs for GBM. In a phone interview, Sidi Chen, an assistant professor at Yale University School of Medicine’s Department of Genetics, pointed to others like the heterogeneity of GBM tumors, which often harbor a diverse population of cells, thereby challenging the use of simply one drug to treat it. Moreover, he said, GBM cells are very plastic, meaning they have the ability to differentiate and infiltrate the normal part of the brain, such that even a highly skilled surgeon would be unable to remove all of them, thereby enabling those that remain to reproduce and cause rapid relapse.

The immune system is another area of interest, he said. While PD-1 inhibitors like Opdivo, which work by turning off the proteins that tell T cells not to kill cancer cells, are straightforward in so-called “hot” tumors like melanoma – meaning those with high mutagenic burdens – the immune-privileged nature of the brain and the low number of T cells that get into it is a challenge. That has led to research on how to get them to enter.

“So simply adding those drugs that have been efficacious in other cancer settings may not be adequate,” said Dr. Wenyin Shi, a radiation oncologist at Jefferson University, in a phone interview. “It may be that the immunosuppressive environment in GBM is more challenging to overcome than in melanoma and so forth.”

Although it is a device rather than a drug, Optune marked the first major advance in improving overall survival in GBM since Temodar. A final analysis of the Phase III study that led to its approval, published in 2017 in the Journal of the American Medical Association, showed that among 695 patients, those treated with the device plus generic Temodar experienced 20.9 months’ overall survival, compared with 16 months for Temodar alone. The percentage of patients alive at five years grew by five points, to 13%.

Shi noted that while Optune requires significant adjustments on the part of patients, who must shave their heads and wear the device at all times, powered by a three-pound battery pack, the rate of compliance is 90% or more.

Although Optune marks a significant advance in GBM treatment, new approaches to drug therapy remain an active area of research in the disease. Barthel pointed to several molecular targets that have drawn researchers attention, such as PTEN, CDKN2A, TERT and EGFR.

And yet, even EGFR has been the subject of failed studies. One of the most spectacular of these was Celldex Therapeutics’ rindopepimut, a peptide cancer vaccine that targeted a form of the protein called EGFRv3. Despite clinical trial data indicating efficacy in patients whose tumors expressed EGFRv3 and a Breakthrough Therapy designation from the FDA – in fact the company even created a brand name, Rintega, before results of the pivotal Phase III trial came in – the vaccine ultimately failed.

Cell therapy approaches are also being explored. In October, City of Hope opened a Phase I clinical trial combining CAR-T cells targeting the antigen IL12Ra2, combined with Opdivo and another BMS immunotherapy drug, the CTLA4 inhibitor Yervoy (ipilimumab). Chen’s lab, meanwhile, is exploring the use of CRISPR gene-editing technology to engineer CAR-T cells against GBM. The cells are in preclinical testing, but he hopes to move them into human subjects in the next two to three years. Still, he and other researchers know the field has a long way to go.

“GBM is one of the toughest cancers – a Holy Grail in the cancer field, maybe along with pancreatic cancer,” Chen said. “But there’s been no significant advancement in GBM over the past two decades.”

Photo: Radachynskyi, Getty Images