‘Dual-target’ CAR-T cell therapy shrinks brain tumours

MRI showing glioblastoma

Targeting two brain tumour-associated proteins – rather than one – with CAR-T cell therapy has shown promise as a strategy for reducing solid tumour growth in patients with recurrent glioblastoma (GBM).

This is according to early results from the first six patients treated in an ongoing Phase I clinical trial led by researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center.

The findings, published in Nature Medicine, suggest that this ‘dual-target’ approach is an encouraging step toward developing effective, long-lasting therapies for solid tumours like GBM.

“This is the first time CAR-T cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma,” said Stephen Bagley, Assistant Professor of Hematology-Oncology, and Neurosurgery, and principal investigator in the clinical trial. “Our results suggest that this is a step in the right direction, and this method, when delivered through a patient’s spinal fluid, could be the key to developing therapies that outsmart the complicated defence systems of GBM.”

The challenge of treating solid tumours with CAR-T

Despite decades of research, there is no known cure for GBM, and approved treatments have limited effect in prolonging an individual’s life expectancy. However, even after aggressive treatment, GBM returns in most patients, which is known as recurrent GBM. The median survival rate for recurrent GBM is less than one year.

CAR-T cell therapy is FDA approved to fight a number of blood cancers, like leukaemia, but researchers have struggled to engineer cells to successfully seek out and kill solid tumours.

“The challenge with GBM and other solid tumours is tumour heterogeneity, meaning not all cells within a GBM tumour are the same or have the same antigen that a CAR-T cell is engineered to attack, and every person’s GBM is unique to them, so a treatment that works for one patient might not be as effective for another,” said Bagley. “What’s more, GBM tumours can evade a patient’s immune system, and block immune cells – both engineered CAR-T cells, and a patient’s own immune cells – that might otherwise fight the tumour. Our challenge is getting our treatment around the tumour’s defences so we can kill it.”

A dual-target approach to glioblastoma

In this trial, researchers used a technology developed in the lab of Donald O’Rourke, the John Templeton Junior Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, and scientific advisor to the trial.

This technique delivers CAR-T cells targeting two proteins commonly found in brain tumours: epidermal growth factor receptor (EGFR), which is estimated to be present in 60% of all GBMs, and interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed in over 75% of GBMs.

While CAR-T cell therapy for blood cancers is typically delivered through an IV, researchers administered these dual-target CAR-T cells into the cerebrospinal fluid, so that the engineered cells could reach the tumours more directly in the brain.

MRI scans 24 to 48 hours after dual-target CAR-T cells targeting EGFR and IL13Rα2 that were administered revealed reduced tumour sizes in all six patients, and these reductions have been sustained out to several months later in a subset of patients.

“We are energised by these results, and are eager to continue our trial, which will give us a better understanding of how this dual-target CAR-T cell therapy affects a wider range of individuals with recurrent GBM,” said O’Rourke. “This cancer is unique in each individual, so a wider range of patients will help us determine the optimal dose, better understand effects like neurotoxicity, and more firmly establish efficacy.”

The researchers report that in all six patients treated with CAR-T cell therapy in this trial, neurotoxicity was substantial but manageable.

Diana Spencer, Senior Digital Content Editor, DDW

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