CRISPR-Built Chimeric Antigen Receptor T Cells are More Potent

CRISPR-Built Chimeric Antigen Receptor T Cells are More Potent

Effective cancer treatments introduce toxic chemicals, involve the surgical removal of tumors, or the administration of doses of radiation, all of which can have serious side effects. However, treatments with antibodies to help the immune system fight cancer cells can also be effective, and cell therapies – the introduction of living cells – are showing great promise.

One form of cell therapy involves the introduction of Chimeric Antigen Receptor (CAR) T cells. Michel Sadelain and his team of researchers at the Memorial Sloan Kettering Cancer Center (MSK) in New York have been pioneering this new immunotherapy technique. Rather than using chemicals or radiation to kill tumors, patients can be provided with exactly the type of immune system cells they need to recognize and attack cancer cells.

To get the CAR T cells to recognize cancer cells they must first be removed from the patient and a new gene must be added to the genome of the cells. When reintroduced, the cells can then recognize that a specific type of cancer cell is foreign and attack it.

The team has been working with CAR T cells as a potential treatment for leukemia and lymphoma, with a new gene added that recognizes the CD19 protein on the surface of B cells. Trials have shown the treatment can be effective. 88% of patients have responded positively to the treatment in a recent trial.

The technique could also be used to treat a range of different cancers. MSK researchers are working on the use of CAR T cells to treat sarcoma and prostate cancer, with plans to also use the technique for the treatment of mesothelioma, lung, breast and ovarian cancer.

Current methods of introducing genes into the T cell genome insert the gene randomly, which can have a range of unwanted effects. During the course of their research, the team discovered that editing the genes of CAR T cells with the CRISPR-Cas9 system made the CAR T cells much more potent, essentially giving the cells more stamina.

The CRISPR-Cas9 gene editing system is a method of introducing new genes or precisely editing DNA. Rather than introducing genes randomly into the genome, researchers can insert the gene at specific points – locations where there is likely to be much less interaction with other active genes.

A Cas9 enzyme is introduced into cells via a deactivated virus (AAV) along with gRNA that binds to a highly specific section of DNA. The Cas9 is then used to make the cut and introduce a new gene.

The researchers found that by inserting the genes using the CRISPR-Cas9 system they could increase the staying power of the T cells. This is important, as Sadelain explained, “Cancer cells are relentless in their attempt to evade treatment, so we need CAR T cells that can match and outlast them.”

The new CRISPR-Cas9 edited cells could be the next generation of CAR T cell therapy. The researchers are currently planning human trials using the new CRISPR-Cas9 edited T cells.

The paper, Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection, was published in Nature on February 22, 2017.

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