Early in-human research shows engineered cell therapy can be useful for solid tumours, but we need more trials.
Car T cell treatment targeting EGFR III has reduced tumour size for three patients with glioblastoma in a first-in-humans trial, according to interim findings published in the NEJM last month.
The genetically engineered cell therapy resulted in rapid tumour regression, albeit short-term.
The three patients – a 74-year-old man with a one-week history of headache and confusion, a 72-year-old man with difficulty reading, and a 57-year-old woman with several weeks of word-finding difficulty and concern for seizure – all had initial tumours positive for the cell surface antigen EGFR variant III.
They all had craniotomy and resection, followed by standard radiation and temozolomide chemotherapy, prior to recurrence of EGFRvIII positive glioblastoma.
The patients’ T cells were engineered to include a synthetic protein which targeted the antigen EGFR and the EGFRVIII variation, and also secreted a molecule that increased the T cells’ ability to engage with it.
Results were “dramatic” for all patients after just one infusion, but tumours recurred for two of them during a short follow-up. The first patient’s tumour showed regression at just day one, but the effect was transient. He received a second infusion on day 37, but by day 72 the tumour had recurred. The second patient had a durable response at day 150, with an 18.5% decrease in tumour cross-sectional area at day two and 60.7% decrease at day 69. The third patient had near complete tumour regression at day five but recurrence within one month.
The recurrences corresponded with dropping levels of CARv3 TEAM-E T cells in those patients, which the authors suggested might be remedied with chemotherapy or more infusions.
Grade three encephalopathy and fatigue were attributed to the treatment. The third patient died 63 days after completing treatment from non-related causes.
“There has been much interest in Car T cells over the last decade with the greatest benefit seen in haematological malignancies,” said Dr Lucy Gately, head of Neuro-Oncology, Cancer Genetics and Clinical Innovation at the Alfred and Cabrini hospitals in Melbourne, and clinical researcher at the Brain Cancer Centre and WEHI.
The use of Car T cell therapy in solid tumours, like glioblastoma, has been limited because they are heterogenous. EGFRvIII, targeted in this treatment, was only present in around 20-30% of glioblastoma tumours, Dr Gately remarked.
“While early results such as these look promising and understandably generate significant enthusiasm, further research and optimisation are essential to achieve robust clinical responses that will improve outcomes for this devastating disease.
“Early success of novel agents rarely translates to phase III clinical trial success in brain cancer,” she cautioned.
An accompanying editorial in the NEJM answered the question “does it work?” with “yes and no”.
The approach used by the researchers “holds a lot of promise,” said one of the commentary authors and an associate of Dr Gately’s at the Brain Cancer Centre, Associate Professor Misty Jenkins AO.
“It’s the first real demonstration that this [approach] can be applied in a place like the brain. And I think this is really just the start of what genetic engineering can do to enhance cell therapies against brain cancer,” Professor Jenkins told OR.
Curing brain cancer would be possible when patients could be quickly diagnosed and administered bespoke treatments that targeted their entire tumour, said Professor Jenkins.
“A monotherapy approach is not really going to work for such a diverse tumour as a brain cancer. These sorts of approaches, armouring, enabling the cell therapies to do more than just recognise one target, is really the future of personalised medicine,” she said.
“The primary target of the CAR is EGFRvIII. What they did though was to engineer the T cell to then secrete other antibodies into the tumour microenvironment that aren’t necessarily as specific so they can target other proteins. Because they’re being delivered straight into the tumour, that enhances efficacy of the cell therapy,” Professor Jenkins explained.
Targeting EGFRvIII was also a good patient safety option, she said, because the mutated protein was only expressed in glioblastoma, so treatment would not prove toxic to other cells.
Establishing the right targets for treatment was currently difficult because there wasn’t yet a proteomic characterisation of glioblastoma tumours, said Professor Jenkins.
“This has been a big problem in cancer biology for decades,” she said.
“IF EVERYTHING WENT REALLY WELL, WE COULD BE INFUSING OUR FIRST PATIENT IN THE NEXT 18 MONTHS.”
Associate Professor Misty Jenkins AO
“We’ve spent billions of dollars sequencing tumours, and that’s taught us so much, but the correlation between DNA and protein is actually very poor. So these tumours can express other red flags that you wouldn’t necessarily detect. We need to be able to map these tumours more comprehensively to identify those targets.”
The sector was turning towards engineering cell therapies, but cell therapy clinical trials were expensive because treatments are personalised and trials take time to set up, she said.
Professor Jenkins has been working on a cell therapy targeting a family of growth receptor proteins.
“But it also targets the tumour vasculature, basically starving them and causing the tumours to melt away,” she said.
“And it’s been incredibly effective to the point of being curative in preclinical models. So now the hard work begins.”
The protocol for a clinical trial was currently being written and work was underway on organising manufacturing and obtaining funding.
“If everything went really well, we could be infusing our first patient in the next 18 months,” Professor Jenkins suggested.
Australia was a good place to conduct clinical trials, but there weren’t enough of them for brain cancer, said Professor Jenkins.
“You have a cohort of patients that have limited options,” she said.
“A diagnosis of glioblastoma is a stage IV terminal illness with a 15-month average survival. Generally these patients are really desperate to find new options and alternatives.”
The Brain Cancer Centre is involved in a world-first regulatory approach which allows drug treatments to be trialled in newly diagnosed patients without waiting for them to undergo the standard of care and then relapse.
“We have to design really innovative trials that enable our clinicians to treat quickly but fail quickly, so that they can then switch the patients to other drugs and other therapies. And that’s a sort of phase zero approach,” said Professor Jenkins.
Professor Jenkins said was confident of a cure for glioblastoma.
“When you look at the progress that’s been made in other cancers like childhood leukemia, or like breast cancer – that used to be a death sentence and now more than 90% survive more than five years – it’s extraordinary the progress we’ve made due to massive investments in medical research,” she told OR.
“So this is not a problem that’s unsolvable. We can solve brain cancer but we’re going to need people and we’re going to need capital.”
