Researchers have developed a prototype for a new kind of cancer immunotherapy. The therapy uses engineered T-cells to target a genetic alteration common among all cancers.
We inherit one version of each gene, known as alleles, from each parent. Often, cancer-related genetic alterations involve the loss of one of these alleles, meaning some cells express just one copy of a gene rather than two. Although a known hallmark of cancer, until now, it has not been possible to hone in on these genes with drugs as the missing allele meant there was nothing for the drugs to target.
Recent advances in immunotherapy and the ability to engineer cancer-fighting T cells to be activated via chimeric antigen receptor (CARs) and then deactivated with inhibitory CARs, however, may change this. With these emerging approaches, researchers can now target missing genes with T cell therapies.
CARs are receptors that are engineered to bind to certain antigens that appear on the surface of cancer cells. In the new approach, known as neoplasm-targeting allele-sensing CAR (NASCAR), CAR binds to and kills cells with missing genes.
NASCAR T cells are engineered to express both activating molecules (CAR) and inhibitory molecules (iCAR). The cells rely on a 'NOT' gate- a term that describes negating the signal of an input- to switch the T cell on or off. As such, it can instruct T-cells on how to behave when encountering both normal cells (with both gene copies) and cancer cells (with a missing gene copy).
This means that if both genes are present in a cell, the inhibitory molecule is activated in the engineered T-cell, and it is ultimately left unharmed. However, if only one gene copy is detected in a given cell, the engineered cells activate, and kill it.
"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," explains Michael Hwang, Ph.D., first author of the paper. "However, in cancer, one allele is lost, so there is no inhibitory or off signal."
So far, the researchers have successfully tested their new NASCAR therapy on three independent cell lines and in mice models. While the researchers say that their study provides a 'proof-of-principle' of their new approach to kill cancer cells, they say that further research over several more years is needed before it can be used in a clinical setting.