CAR T treatment utilises the body’s own disease-fighting T cells, which are fortified and multiplied in a lab, and then reinjected into the body to fight the cancer. — 123rf.com
In recent years, cancer researchers have hailed the arrival of chimeric antigen receptor T-cell (CAR T) therapy, which has delivered promising results, transforming the fight against various forms of cancer.
The process involves modifying patients’ T-cells to target cancer cells, resulting in remarkable success rates for previously intractable forms of cancer.
Six CAR T therapies have secured US Food and Drug Administration (FDA) approval to date, and several more are in the pipeline.
However, these therapies come with severe and potentially lethal side effects, namely, cytokine release syndrome (CRS) and neurotoxicity.
These drawbacks manifest as a range of symptoms – from high fever and vomiting to multiple organ failure and patient death – posing significant challenges to broader clinical application.
Now, a University of Pennsylvania research team in the United States, led by School of Engineering and Applied Science associate professor Dr Michael Mitchell, has found a solution that could help CAR T therapies reach their full potential while minimising severe side effects.
Their findings were published in the journal Nature Materials.
“Addressing CRS and neurotoxicity without compromising the therapeutic effectiveness of CAR T cells has been a complex challenge,” says Assoc Prof Mitchell.
He explains that unwanted interactions between CAR T and immune cells called macrophages drive the overactivation of macrophages, which in turn result in the release of toxic cytokines that lead to CRS and neurotoxicity.
“Controlling CAR T–macrophage interactions in vivo (i.e. in the body) is difficult,” he says.
“So, our study introduces a materials engineering-based strategy that involves incorporating a sugar molecule onto the surface of CAR T cells.
These sugars are then used as a reactive handle to create a biomaterial coating around these cells directly in the body, which acts as a suit of armour, preventing dangerous interactions with macrophages.”
Study first author and postdoctoral researcher Dr Gong Ningqiang elaborates on the technique: “We attached this sugar molecule to the CAR T cells using metabolic labelling.
“This modification enables the CAR T cells to attack cancer cells without any hindrance.
“When symptoms of CRS begin to manifest, we introduce another molecule – polyethylene glycol (PEG) – to create the suit of armour, which effectively blocks dangerous interactions between these engineered T-cells, macrophages and the tumour cells themselves.”
Over time, small tumour antigens can still reach what the researchers call “PEGylated CAR T cells”, slowly activating and expanding them without triggering the severe side effects associated with rapid activation and expansion.
As the CAR T cells slowly expand, the surface density of PEG becomes diluted, progressively restoring their ability to interact with other cells.
The team says that their approach offers more than just a safety net for patients, it also opens up a new “therapeutic window” for treatment.
This is made possible, Dr Gong says, due to the size differences among tumour cells, CAR T cells, and macrophages.
He explains that tumour cells and CAR T cells are typically smaller (ranging from 5-10 micrometres), compared to macrophages (>20 μm), and as the surface density of PEG on CAR T cells begins to dilute, interactions between CAR T cells and tumour cells are restored before interactions with macrophages.
This restoration, Assoc Prof Mitchell says, allows CAR T cells to target and kill cancer cells without causing macrophage overactivation, thereby minimising the risk of dangerous CRS symptoms and neurotoxic effects.
“By incorporating the PEG buffer, we’ve successfully managed to modulate the interactions between CAR T cells and macrophages.
“This enables a therapy that is both safer and effective,” he says.
Beyond this, the team is also examining the potential for in situ “PEGylation” to be applied to other types of cellular immunotherapies, and even broader applications.
“The implications could be far-reaching,” says Assoc Prof Mitchell.
“We’re looking at a potentially universal approach to making cellular therapies safer for all patients.”
