A ‘clinical graveyard’ no more? Research offers hope in treating refractory glioblastoma

Glioblastoma is one of the most aggressive brain tumours in adults. There’s really no efficacious treatment for tumours that return and it has a poor history of drug development. But Canadian and American researchers have identified a new signalling pathway that is a strong contender for a new treatment: chimeric antigen receptor (CAR) T-cell therapy that targeted the pathway in mice models showed significant benefits.“If you look at the history of drug development with glioblastoma, it’s a very bleak picture. Some people in talks will call it ‘a clinical graveyard,’” explained Dr. Sheila Singh, co-senior author of the paper and a professor with McMaster University’s department of surgery and director of the Centre for Discovery in Cancer Research. “We’ve only had four drug approvals in the past 100 years.”The reason why there’s been little progress is researchers have “been going over the same handful of targets for several decades” she told the Medical Post. Dr. Singh and colleagues investigated a new signalling pathway. First, they used gene editing techniques to identified a protein, Roundabout Guidance Receptor 1 (ROBO1), that helps guide certain cells during axonal development.“In glioblastoma, we believe that the tumour hijacks this signalling pathway and uses it to invade and infiltrate the brain,” Dr. Singh explained in a McMaster University press release. “If we can block this pathway, the hope is that we can block the invasive spread of glioblastoma and kill tumour cells that cannot be removed surgically.” To test the theory, Kevin Henry and Martin Rossotti at the National Research Council Canada developed antibodies to ROBO1. This allowed Dr. Singh and colleagues to create CAR T cells using the antibodies to ROBO1. “We created a type of cell therapy where cells are taken from a patient, edited and then put back in with a new function. In this case, the CAR T cells were genetically edited to have the knowledge and ability to go and find ROBO1 on tumour cells in animal models,” said` lead author Chirayu Chokshi, a former PhD student who worked alongside Dr. Singh at McMaster University.The CAR T cells were used in mice models of refractory glioblastoma. The mice models were developed using transplanted human tissue samples from neurosurgical patients. Dr. Singh is a pediatric neurosurgeon and often knows the patients who donated tissue. She told the Medical Post it was a real privilege to see both sides of the process, “to know the patients and understand their clinical scenario,” and then go to the lab and study “the scientific part of things.”Read: How the power of mRNA can be harnessed for cancerThe mouse models of adult glioblastoma treated with CAR T-cell therapy showed a reduced tumour burden and a doubling in median survival time compared to mice who were treated with control T cells. “These findings are highly original and innovative, and could pave the way to potential impactful novel CAR T-cell therapies for glioblastoma,” wrote Dr. Denis Migliorini, professor of medicine and glioblastoma researcher at the University of Geneva, Switzerland, in a research briefing.The researchers also tested the CAR T-cell therapy in pediatric medulloblastoma and adult lung-to-brain metastasis mice models. In those models, CAR T-cell therapy eradicated tumours in 50%-to-100% of the mice. CAR T-cell therapy has been used in solid cancers but not often in brain cancers. There have been a number of "first in man” cases of CAR T-cell therapy studies in the brain, and the outcomes have been fascinating, Dr. Singh said. The findings provide a glimmer of hope to glioblastoma patients, Dr. Singh said. “I’m hoping a paper like this will not only inspire patients and caregivers, and healthcare workers taking care of these patients, but also people in industry who are responsible for funding drug development,” she said. The lack of success in glioblastoma drug development also means it’s hard to attract industry funding for new therapeutics in this area.The next step is to find an industry partner to create clinical-grade CAR T-cells, Dr. Singh said. The researchers are currently designing a clinical trial.The research and a research briefing are published in Nature Medicine. It was dedicated to the memory of Cindy Lee Graham, Mackenzie Rigg and “all the patients with brain tumors who donated tissues and cells to this research program,” lead author Chokshi wrote.The research was co-led by Jason Moffat, head of the Genetics and Genome Biology program at the Hospital for Sick Children in Toronto.Read: Tumours are losers! Queen's docs and med students to face off in hockey showdown

A ‘clinical graveyard’ no more? Research offers hope in treating refractory glioblastoma

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