In recent years, cancer researchers have cheered the arrival of chimeric antigen receptor (CAR) T-cell therapy, which has achieved encouraging results and changed the treatment methods of various cancers. CAR-T cell therapy targets cancer cells through genetically modified patients’ T cells, thereby achieving a significant cure rate for previously incurable cancers.
Currently, six CAR-T cell therapies have been approved by the US Food and Drug Administration (FDA), and several are under development. However, these cell therapies also have serious potential fatal side effects, namely cytokine release syndrome (CRS) and neurotoxicity. These side effects manifest as a series of symptoms – from high fever and vomiting to multiple organ failure and patient death – posing significant challenges for wider clinical applications.
Now, in a new study, researchers from the University of Pennsylvania in the United States have found a solution that may help CAR-T cell therapy fully realize its potential while minimizing serious side effects. The relevant research results were published in the journal Nature Materials, with the title “In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity”. The corresponding author of the paper is Dr. Michael Mitchell, Associate Professor at the School of Engineering and Applied Sciences at the University of Pennsylvania.
“Addressing CRS and neurotoxicity issues without affecting the efficacy of CAR-T cell therapy has always been a complex challenge, “Mitchell said
He said that unwanted interactions between CAR-T cells and immune cells called macrophages can lead to excessive activation of macrophages, leading to the release of toxic cytokines, leading to CRS and neurotoxicity.
Mitchell said it is tough to control the interaction between CAR-T cells and macrophages in the body. Therefore, our study introduces a strategy based on material engineering, which involves adding sugar molecules to the surface of CAR-T cells. These sugar molecules are then used as reaction stems to form a biomaterial coating directly around these cells in the body, which acts like an ‘armor’ to prevent dangerous interactions with macrophages.
The co-first author of the paper and postdoctoral researcher at Mitchell Laboratory, Ningqiang Gong, detailed this technique: “We use metabolic labeling technology to attach sugar molecules to CAR-T cells. This modification allows CAR-T cells to attack cancer cells without any hindrance. When CRS symptoms begin to appear, we introduce another molecule – polyethylene glycol (PEG) – to create armor, effectively blocking the dangerous interactions between genetically modified T cells, macrophages, and tumor cells themselves.”
Over time, small tumor antigens can still reach what the authors call “PEGylated CAR-T cells”, slowly activating and amplifying them without causing serious side effects related to rapid activation and amplification. As CAR-T cells slowly expand, the surface density of PEG will be diluted, gradually restoring their ability to interact with other cells.
These authors stated that their method not only provides a safety net for patients, but also opens up a new “treatment window” for treatment.
Gong said that the reason for achieving this is due to the different sizes of tumor cells, CAR-T cells, and macrophages. He said that compared to macrophages (greater than 20 microns), tumor cells and CAR-T cells are usually smaller (ranging from 5 microns to 10 microns). As the PEG density on the surface of CAR-T cells begins to dilute, the interaction between CAR-T cells and tumor cells will be restored before they interact with macrophages.
Mitchell said that this recovery could enable CAR-T cells to target cancer cells without causing excessive activation of macrophages, thereby minimizing the risk of dangerous CRS symptoms and neurotoxic effects.
Mitchell said, “By adding PEG buffer, we successfully regulated the interaction between CAR-T cells and macrophages. This makes treatment safer and more effective.”
In addition, these authors are also exploring the possibility of applying in situ PEGylation to other types of cellular immunotherapy or even more widely. Mitchell said, “This could have profound implications. We are studying a potential universal method to make cell therapy safer for all patients.”
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Reference
Ningqiang Gong et al. In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity. Nature Materials, 2023, doi:10.1038/s41563-023-01646-6.