Ludwig Johns Hopkins researchers develop a prototype CAR T cell therapy that targets loss of a gene copy

MARCH 19, 2021, NEW YORK – Researchers led by Ludwig Johns Hopkins Co-director Kenneth Kinzler and investigator Shibin Zhou have developed a prototype for a new cancer immunotherapy that uses engineered chimeric antigen receptor (CAR) T cells to target a common genetic aberration associated with cancers. The approach stimulates a CAR T cell attack of cancer cells that lack expression of one of the usual two copies of a gene, a phenomenon known as loss of heterozygosity (LOH).

The study was reported March 15 in the Proceedings of the National Academy of Sciences.

“This copy loss, or LOH, is one of the most common genetic events in cancer,” said Kinzler, who is also a professor of oncology at Johns Hopkins University.

“Historically, these missing gene copies, although a hallmark of cancer, have not been good therapeutic targets because the protein is missing. There is nothing to target with a drug,” Kinzler explained. The new approach, he said, stems from the ability to engineer cancer-killing T cells that can be activated with chimeric antigen receptors (CARs) and deactivated with inhibitory chimeric antigen receptors (iCARs). CARs are engineered receptors introduced to T cells that bind to specific antigens-or telltale molecules that alert the immune system-on the surface of target cells. The researchers named their approach NASCAR, for “neoplasm-targeting allele-sensing” CAR.

The NASCAR T cell is engineered to express an activating molecule (CAR) and an inhibitory molecule (iCAR). The approach relies on a “NOT” gate to control the CAR T cell. A NOT gate is a computational term used to describe an event that negates the signal of an input. If both gene copies (or alleles)-A and B-are expressed on a cell encountered by the NASCAR T cell, the inhibitory CAR is simultaneously activated, and the presumably normal cell is left untouched. If, however, one allele is present and the other missing-A and not B-the NASCAR T cell is activated to kill the deficient and thus cancerous cell.

The researchers successfully tested their NASCAR T cell therapy in three independent cell lines and in mouse models. This included models with and without loss to confirm the specificity of the approach to the targeted genetic alteration. For these studies, the researchers devised NASCAR T cells to target the loss of cell surface molecules known as HLA, but they plan to expand the approach to other genes often subject to LOH. Ongoing research will also focus on equipping the NASCAR T cells with more precisely regulated CARs and iCARs.

“This study provides proof-of-principle that this approach can be used to selectively kill cancer cells,” said Zhou, who is also associate professor of oncology at Johns Hopkins, adding that several more years of testing will be required before the approach can be implemented clinically.

The news release from which this summary is derived can be found here.

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