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CRISPR Editing Creates TCR Swap-Shop for Cancer Immunotherapy

A team at Cardiff University in the U.K. has used CRISPR/Cas9 genome editing to generate engineered killer T cells that are up to a thousand times more sensitive to cancer cell antigens than T cells engineered using more conventional approaches, and which allowed far better targeting of T cells to cancer cell lines and patient-derived leukemia cells.
The new approach exploits the genome editing technology to remove the T cells’ endogenous T cell receptors (TCRs), and simultaneously replace them with cancer antigen-specific TCRs. The researchers, led by Cardiff University School of Medicine’s Professor Andrew Sewell and Dr. Matesuz Legut, hope that the new method will enable the development of far more effective anticancer immunotherapies, and offer up a new experimental system for identifying novel cancer targets.
“The T-cells we made using genome editing do not have any of their own T-cell receptors left, and therefore the only receptor they can use is the one specific for cancer,” Dr. Legut comment. “As a result, these cells can be a thousand times better at seeing and killing cancer than the cells prepared using the current methodology.”
The researchers report on their studies in Blood, in a paper entitled, “CRISPR-mediated TCR replacement generates superior anticancer transgenic T-cells.”
TCRs in vertebrates exist as heterodimers composed of either αβ or γδ TCR chains. While the αβ TCRs generally recognize foreign antigenic peptides presented by major histocompatibility complex (MHC) molecules on antigen presenting cells, γδ TCRs tend to recognize cell surface targets, including cancer antigens, the researchers explain.
Traditional approaches to engineering T cells for cancer immunotherapy involve the transduction of cells with a chimeric antigen receptor (CAR) or a TCR for a specified antigen. The methods used effectively add the cancer antigen receptor to T cells that already express their own native receptors. But the presence of these pre-existing endogenous TCRs reduces the number of cancer-specific TCRs that can be inserted into the T cells, and also creates the potential for generating hybrid TCRs that can trigger potentially fatal autoimmunity.
“Up until now, T cells engineered to fight cancer had two kinds of receptors – the therapeutic one that was added in the lab, and their own naturally existing one,” notes Dr. Legut. “Since there is only limited ‘space’ on a cell for receptors, cancer-specific ones need to compete with the cell’s own receptors to perform their function. More often than not, the cell’s own receptors win that competition, and leave ‘space’ for only a very limited number of newly introduced, cancer-specific receptors, which means that T-cells engineered with the current technology never reach their full potential as cancer killers.”

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CRISPR Editing Creates TCR Swap-Shop for Cancer Immunotherapy

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