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Genome Editing Enhances CAR T-Cells to Fight Cancer

Gene editing illustration

(NIH.gov)

21 November 2017. A process using genome editing is shown to bolster cancer-fighting properties of T-cells from the immune system already modified to attack cancer cells. A team from Cardiff University in Wales, U.K. describes its methods in a paper published earlier this month in the journal Blood (paid subscription required).

An emerging technology for cancer treatments uses T-cells, white blood  cells from the patient’s immune system, genetically engineered to express chimeric antigen receptor proteins. The therapies reprogram the T-cells with genetic engineering to find and kill cancer cells like an antibody. These modified chimeric antigen receptor or CAR T-cells are infused back into the patient, seeking out and binding to targeted proteins found on the surface of B cells — another type of white blood cell — associated with several types of blood-related cancers.

CAR T-cells are being tested in clinical trials among patients who do respond to conventional treatments for a number of blood-related cancers, which report remission rates as high as 90 percent. In August 2017, FDA approved the first CAR T-cell treatments in the U.S. for patients with a form of stubborn or relapsing acute lymphoblastic leukemia. As reported in Science & Enterprise, researchers are also adapting these techniques to solid tumor cancers.

A team from the Cardiff lab of immunologist Andrew Sewell is seeking better methods for finding and attacking cancer cells with CAR T-cells. In some cases, a patient’s T-cells have limited capacity for adding additional receptors, which also limits their therapeutic ability. Project leader Mateusz Legut and colleagues looked to the genome editing technique known as Crispr, for clustered regularly interspaced short palindromic repeats, as a way to add more capacity to T-cells.

For their genome editing, the researchers used an enzyme known as Crispr-associated protein 9 or Cas9. RNA molecules guide the Cas9 editing enzyme to specific genes needing the fix. “The T-cells we made using genome editing do not have any of their own T-cell receptors left,” says Legut in a university statement, “and therefore the only receptor they can use is the one specific for cancer.”

The team tested the engineered and genome-edited T-cells on blood cancer cell lines from patients, and compared the results to modified T-cells for therapy without genome editing. The genome-edited CAR T-cells, say the authors, express many more transgenic T-cell receptors, which strengthens their cancer-fighting ability. In their tests, the genome-edited T-cells are shown to be much more sensitive to their antigen targets than the non-edited cells. “As a result,” notes Legut “these cells can be a thousand times better at seeing and killing cancer than the cells prepared using the current methodology.”

The authors conclude the combination of CAR T-cells and genome editing opens the door to a new type of cancer immunotherapy. Cardiff hematologist and co-author Oliver Ottmann adds, “I believe that our improved method of making cancer-specific T-cells will guide a new generation of clinical trials and be used by researchers in the laboratory to discover new cancer-specific T-cell receptors and new targets for cancer therapy.”

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