Researchers have developed a prototype for new cancer immunotherapy that uses engineered T cells to target genetic modification that is common among all cancers. The method, which stimulates an immune response against cells that lose a single gene copy, called heterozygosity loss (LOH), was developed by researchers at the Ludwig Center, Lustgarten Laboratory and the Bloomberg ~ Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Kimmel Cancer Center.
Genes have two alleles, or duplicates, with one copy obtained from each parent. Cancer-related genetic modifications usually involve the loss of one of these gene copies.
This copy loss, or LOH, is one of the most common genetic events in cancer. “
Kenneth Kinzler, Ph.D., Associate Director, Ludwig Center, Professor of Oncology and Director of Research
The new method of cancer immunotherapy counteracts the required gene replication to an immune cell signal. “Historically, the missing gene copies, although a sign of cancer, have not been functional therapeutic targets because the protein is missing. There is nothing to target with a drug,” he explained. Kinzler. Immunotherapy, however, and the ability to induce cancer-killing T cells were activated by chimney antigen receptors (CARs) and suppressed or suppressed by inhibitory chimney antigen receptors ( iCARs), making it possible to target LOH with T cells, he says.
These findings were reported March 15 in the Proceedings of the National Academy of Sciences.
CARs are engineered receptors that bind to specific antigens on the surface of cancer cells. The antigen is a red flag of a type that signals a cancer cell for destruction. In this procedure, the CAR binds to and kills cells with LOH. The researchers described their NASCAR approach, for a CAR targeting a neoplasm.
The NASCAR T cell is engineered to express active molecule (CAR) and inhibitory molecule (iCAR). The procedure relies on a “NOT” gate to turn the T cell on or off. Gate NOT is a computer term used to describe the rejection of an input signal. For this method of immunotherapy, it instructs the engineered T cell whether it should activate when you encounter a normal cell or a cancer cell.
If both gene copies – A and B – are present – the blocking molecule is activated, and the engineered T cells do nothing for the normal cell. If one gene copy is present and the other is missing – A and not B – 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 fact – turn off their together, “explained Michael Hwang, Ph.D., a graduate student at Johns Hopkins University School of Medicine and first author. “However, in cancer, one allele is missing, so there is no obstruction signal, or offline.” The researchers created artificial receptors – the CAR and iCAR – that are able to differentiate proteins expressed from one of the two alleles.
“The cancer cell needs to express allele A and not allele B to activate the NASCAR T cell,” explained Brian Mog, MD / Ph.D. candidate at Johns Hopkins University School of Medicine and co-author.
The researchers successfully developed their NASCAR treatment in three independent cell lines and also in mouse models. This included models with and without LOH to determine the specificity of the approach to genetic modification. For their laboratory studies, the researchers used HLA genes, but plan to extend the approach to other LOH-receiving genes. Ongoing research will also focus on improved versions of these engineered T cells with more precisely regulated CARs and iCARs.
“This study provides confirmation of a principle that this approach can be used to selectively kill cancer cells,” said Shibin Zhou, Ph.D., associate professor of oncology and co-director study, adding that it requires several more years of testing before it can be clinically implemented. “Assembling and fully testing all the parts is a long and complex process.”
The new discovery builds on more than three decades of study by Kinzler and co-director of the Ludwig Center Bert Vogelstein, MD, which first identified the genetic changes that contribute to the development and growth of cancer and that -now developing new ways to use these changes as therapeutic targets. .
“In recent years, it has become clear that the immune system is a powerful tool against cancer,” says Kinzler. Their focus now, he says, is to develop new immunotherapies that can target the genetic changes that differentiate cancer cells from normal cells with the goal of extending the benefit of immunotherapy to many more patients.