Sen. John McCain leaves a meeting of GOP senators in the U.S. Capitol June 22, 2017.
On Wednesday, Mayo Clinic released a statement revealing that longstanding Republican Senator John McCain has an aggressive form of brain cancer.
Called glioblastoma multiforme (GBM), it’s responsible for around 15 percent of the 79,000 brain cancers diagnosed in America each year. Former Vice President Joe Biden’s son, Beau, succumbed to the same disease in 2015.
Brain cancers are always a challenge to treat, noted Jeffrey Bacha, cofounder and CEO of DelMar Pharmaceuticals, which has an investigational GBM drug in Phase 3 trials.
“Unfortunately, there have been no real drug approvals in the field of glioblastoma for decades,” he said via phone.
Many roadblocks have shut down scientists’ best efforts. There’s the blood-brain barrier to contend with, there is ample blood flow to the tumor, and the surrounding area is vitally important for function and survival. The tumor is also very heterogeneous, Bacha explained, which means different regions won’t respond to the same targeted therapies.
“Even the immunotherapies that have been looked at in GBM have not lived up to the promise that everybody hoped they would have,” he said.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
Needham, Massachusetts-based Celldex Therapeutics gave the cancer vaccine approach a commendable effort. It made it all the way to Phase 3 trials and had reportedly even begun mapping out its manufacturing plans. Unfortunately, an interim data analysis in early 2016 showed the therapy wasn’t extending the lifespan of those treated.
FDA approved checkpoint inhibitors aren’t a good fit either: Glioblastomas don’t typically express the key targets, such as PD-L1, at any significant level.
That said, it’s too soon to write-off immuno-oncology interventions.
On Wednesday, the same day McCain’s diagnosis was revealed, a paper was published in the journal Science Translational Medicine discussing a CAR-T approach to treating glioblastoma.
CAR-T therapies have delivered phenomenal results in refractory blood cancers. Work in solid tumors is further behind and for brain cancers, there are many added layers of complexity.
Scientists from the University of Pennsylvania’s Perelman School of Medicine, Novartis (the current leader in the CAR-T space), and Massachusetts General Hosptial were undeterred.
In a first-in-human pilot study, 10 patients with heavily treated, refractory GBM had their T-cells engineered to attack EGFR variant III, a growth factor expressed in approximately 30 percent of newly diagnosed GBM cases.
It’s a start, but as noted by Bacha, targets tend to be unevenly expressed throughout glioblastomas.
“The major barriers to clinical efficacy of this therapy are the heterogeneity of EGFRvIII expression and the inhibitory tumor microenvironment, which becomes even more immunosuppressive after CART cells,” the study authors noted.
Nonetheless, they concluded that the study “demonstrated that manufacturing of CART-EGFRvIII cells from patients with recurrent GBM is feasible and that there was no cross-reactivity of wild-type EGFR with our construct.”
With just 10 patients, no conclusions about its clinical benefit could be drawn,
“But we observed that CART-EGFRvIII cells infused intravenously did traffic to the brain tumor and exert antigen-directed activity,” the authors wrote.
In the meantime, surgery, radiation, and chemotherapies remain the standard of care, with a sprinkling of medical devices.
DelMar Pharmaceuticals is focusing its attempts around MGMT, a DNA repair enzyme. As many as two-thirds of GBM patients have an unmethylated MGMT promoter gene, which makes the tumor more resistant to radiation and temozolomide.
DelMar’s lead small molecule asset, VAL-083 (dianhydrogalactitol), eliminates MGMT from the equation because it attacks the tumor differently than current frontline chemotherapies.
The harsh reality is that gains are typically measured as a matter of months. Yet Bacha stressed that these can still be very meaningful and in rare cases, patients defy all odds and live for years after their diagnosis.
“Whenever we hear about someone who is diagnosed, we think back to those stories and the people that we know who have beaten the disease — as few and far between as they are,” Bacha said. “As someone who has lived through so many things… [McCain] might be lucky enough to be one of the few who do beat the disease.”
Photo: Chip Somodevilla/Staff, Getty Images
