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Gene Editing Deactivates Cause of T-Cell Side Effects

Human T-cell

Scanning electron micrograph of a healthy human T-cell (NIH.gov)

26 Feb. 2019. A biotechnology company developing engineered T-cells as treatments for cancer, used gene editing to deactivate a likely cause of serious adverse effects from its therapies. A team from Cellectis Inc. in New York and Paris describe their discovery in yesterday’s issue of Journal of Biological Chemistry.

Cellectis develops cancer treatments that harness the immune system by breaking down defenses tumors create to prevent the body’s immune system from fighting the disease. The company’s platform builds on recent developments that take T-cells, white blood cells from the immune system, and reprogram the cells through genetic engineering to find and kill cancer cells. The engineered T-cells become hunter cells, containing proteins known as chimeric antigen receptors that act like antibodies. These modified chimeric antigen receptor or CAR T-cells are infused into the patient, seeking out and binding to proteins associated with the cancer.

Most current CAR T-cell methods genetically engineer a patient’s own T-cells, then re-infuse the altered T-cells back into the individual. Cellectis’s process is designed to produce off-the-shelf CAR T-cell treatments, it calls Universal CAR T-cells, or UCARTs. These treatments use T-cells from healthy donors, rather than a patient’s own T-cells, then are genetically engineered to match the attributes of specific cancer types.

A continuing problem with CAR T-cell cancer therapies, however, is high rates of adverse effects, often from cytokine release syndrome, the release of a large volume of immune system proteins into the blood stream. While most patients experience mild reactions, such as headache or fever, other recipients of CAR T-cell treatments report more serious, even life-threatening reactions leading to deaths of some patients. While the symptoms can be treated and relieved, the Cellectis team led by the company’s R&D team leader Julien Valton, is seeking ways of preventing cytokine release syndrome in the first place.

Valton and colleagues analyzed reactions of CAR T-cells in the lab to identify the cytokines released when the engineered T-cells interact with therapeutic targets. The analysis led to identifying a protein, granulocyte-macrophage colony-stimulating factor or GMCSF, as the main culprit in stimulating cytokine release syndrome. The researchers observed GMCSF is released before other proteins and in greater quantities in CAR T-cell interactions.

The team used Cellectis’s gene-editing technology known as Talen, short for transcription activator-like effector nucleases, to knock out the gene that codes for GMCSF. Unlike the more well-known Crispr genome-editing process, Talens are synthetic enzymes that Cellectis says provide highly precise editing of genomes. The researchers report that editing out the gene responsible for GMCSF, not only stopped production of that cytokine, but also other inflammatory enzymes produced with cytokine release syndrome, or CRS.

The researchers then tested the anti-tumor effectiveness of CAR T-cells edited to remove the GMCSF gene with tumor cells from 4 different donors. The results show the edited CAR T-cells retain their anti-tumor capabilities, even with a 90 percent reduction in GMCSF secretions, providing a potentially safer form of CAR T-cell treatments for cancer patients.

Valton says in a company statement that, “we investigated the biogenesis of CRS and based on our findings, developed a CAR T-cell product candidate that could potentially prevent rather than treat CRS symptoms. We hope this approach can bypass CRS symptomatic treatments and improve the overall safety of CAR T-cell therapies for cancer patients.”

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