An improved way of engineering immune cells to fight cancers and other conditions could make them safer and more effective. It would also allow doctors to pause the treatment if someone had severe side effects.
“It could give an extra level of control over the systems,” says at the University of Pittsburgh, Pennsylvania. “We’re excited about the additional safety.”
CAR T-cells are immune cells that are genetically engineered to attack specific targets in people’s bodies. They have proven highly effective against leukaemia, with several treatments already approved.
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Recent results have shown CAR T-cells could help treat many conditions other than cancer. For instance, last year it was reported that five people with the autoimmune condition lupus were successfully treated with CAR T-cells.
CAR T-cells are created by extracting immune cells from a person’s blood and using a virus to add a gene. This gene encodes a receptor that protrudes from the outside of the cell and binds to a specific protein. When the receptor binds to its target – usually a protein found on the outside of cancer cells – it sends an attack signal, triggering the CAR T-cell to kill the cell it is bound to.
But around 80 per cent of people on CAR T-cell therapies have severe side effects. One reason is that it is hard to find proteins specific to cancer cells, so CAR T-cells may attack healthy cells that have the target protein.
Attacking T-cells also release signals to summon help, and this can trigger a life-threatening overreaction of the immune system known as a cytokine storm.
Lohmueller and his colleagues are one of several teams trying to make CAR T-cell treatments safer using proteins called adapters. In this approach, the receptor doesn’t bind directly to the target protein, but instead has a slot for an adapter, which does bind to the target protein. The adapter can be injected gradually in several doses after the CAR T-cells have established in the body, and the doses paused if people develop side effects.
Last year a company called Calibr reported promising results from a trial of this approach, with compared with five to 17 days for those given conventional CAR T-cells.
Lohmueller’s team has now taken the approach further by creating adapters that have an “off” switch. These adapters can be chemically altered by a drug so they no longer fit in the slot on the receptor. If a person develops serious side effects, injecting the drug should stop the CAR T-cells attacking.
So far, this approach has only been tested on cells in the lab, but the experiments show it can also be used to stop CAR T-cells attacking one target protein while continuing to attack another. This would allow doctors to safely test new therapies, Lohmueller says.
Some groups have created CAR T-cells with kill switches, but killing the cells stops the treatment altogether. With Lohmueller’s approach, the CAR T-cells can be reactivated at any time by injecting another dose of adapters, he says.
His team is also developing “on” switches for adapters so that CAR T-cells will bind to the target protein only in specific environments, such as those low in oxygen or highly acidic.
These conditions are found in many solid tumours, meaning such CAR T-cells should be better at targeting cancerous cells while leaving healthy ones unharmed. So far, efforts to use CAR T-cells to treat solid cancers have been unsuccessful, in part because of the difficulties of finding targets specific to the tumours.
“Although this work is at an early stage, cleavable off-switch adapters may provide a lever to better control these living drugs,” says at the University of Pennsylvania. “Patient safety is paramount as new CAR T-cell therapies are developed and deployed.”
bioRxiv
