CAR T-Cell Immunotherapy Approach Targets Common Genetic Alteration

A new type of cancer immunotherapy using engineered T cells has been found to target a genetic alteration common across all cancers, according to researchers at the Ludwig Center, the Lustgarten Laboratory, and the Bloomberg-Kimmel Institute for Cancer Immunotherapy.

The approach stimulates an immune response against cells that are missing 1 gene copy, called loss of heterozygosity, according to a press release. Although most genes have 2 alleles, cancer-related genetic alterations commonly involve the loss of 1 of these gene copies, known as loss of heterozygosity (LOH).

“This copy loss, or LOH, is one of the most common genetic events in cancer,” said study leader Kenneth Kinzler, PhD, co-director of the Ludwig Center, in the press release.

The novel immunotherapy approach inverts this missing gene copy into an immune cell-activating signal. These missing alleles have not historically been a therapeutic target with drugs because the protein is missing, according to Kinzler. Immunotherapy and chimeric antigen receptor (CAR) T-cell therapy, specifically, has now made it possible to target LOH with T cells, according to the press release.

CARs are engineered receptors that bind to specific antigens on the surface of cancer cells, which mark the cancer cell for destruction. In the new approach, the CAR binds to and kills cells with LOH. The researchers named their approach neoplasm-targeting allele-sensing CAR (NASCAR).

NASCAR T cells are engineered to express an activating molecule (CAR) and an inhibitory molecule (iCAR). The approach relies on a “NOT” gate—a term used to describe negating the signal of an input—to turn the T cell on or off.

For the NASCAR approach, the gate instructs the engineered T cell whether or not to take action upon encountering a normal cell or a cancer cell. If both gene copies are present, the inhibitory molecule is activated, whereas if 1 gene copy is present and the other is missing, the engineered T cells are activated and kill the cancer cell.

“In normal cells where both alleles are present and expressed, the NASCAR T cells simultaneously receive both on and off signals that—in essence—cancel each other out,” said first author Michael Hwang, PhD, in the press release. “However, in cancer, one allele is lost, so there is no inhibitor, or off signal.”

The investigative team successfully tested their NASCAR therapy in 3 independent cell lines and models both with and without LOH to confirm the specificity of the approach. For their laboratory studies, the team used HLA genes, but they plan to expand the approach to other genes that undergo LOH. Ongoing research will also explore potentially improved versions of these engineered 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 study co-leader Shibin Zhou, PhD, in the press release.

He added that it will take several more years of testing before the approach can be implemented clinically.

“It is a long and complex process to assemble and fully test all of the components,” Zhou said.

The new findings build off of more than 30 years of research, during which time investigators identified the genetic alterations that contribute to cancer development and growth. Researchers are now developing new ways to use these alterations as therapeutic targets.

“In recent years, it has become clear that the immune system is a powerful tool against cancer,” Kinzler concluded in the press release.

He said their focus now is to develop new immunotherapies that can target the genetic alterations that distinguish cancer cells from normal cells with the goal of extending the benefits of immunotherapy to a wider patient population.

REFERENCE

Cancer Immunotherapy Approach Targets Common Genetic Alteration [news release]. Johns Hopkins Medicine; March 16, 2021. https://www.hopkinsmedicine.org/news/newsroom/news-releases/cancer-immunotherapy-approach-targets-common-genetic-alteration. Accessed March 16, 2021.