Novel CAR-T-cell therapy may be promising treatment for brain cancer

Gene therapy research from UCSF may one day cure glioblastoma multiforme, the deadliest form of brain cancer

By NAREN KRISHNA JEGAN — science@theaggie.org

Immunology is the study of the body’s various defense mechanisms. One main focus in this area of research is how to create defense mechanisms against malignant tumors, such as glioblastoma multiforme (GBM), one of the most aggressive forms of brain cancer. With recent advances through a new form of cell therapy, researchers aim to mitigate the deadly impact of GBMs — which could potentially lead to a long-awaited cure.

The University of California, San Francisco (UCSF) researchers Hideho Okada and Wendell Lim have developed a novel treatment platform that may have successful implications in curing brain cancer.
One of the many types of immune cells in the body is the T cell, a white blood cell whose job is to destroy harmful pathogens. T cells originate in the bone marrow and then move to the thymus, where they undergo a “training camp” to naturally select the strongest and most effective cells. This is determined by their ability to bind onto specific antigens while recognizing and not attacking endogenous antigens. They are critical for the regulation of pathogens and have been studied extensively over the past few decades.

CAR-T therapy is a new form of treatment that utilizes this behavior of T cells. To administer this treatment, first a patient’s blood is drawn to separate the T cells from other immune cells and blood components. These cells are then treated with a deactivated, harmless virus that carries genetic code for the cell to develop a new receptor.

This receptor, called a chimeric antigen receptor (CAR), is used to train the modified CAR-T cells to recognize tumor cells, markers and pathogens. In comparison to traditional immunotherapeutic methods, CAR-T-cell therapy provides treatment over a longer period of time. Furthermore, the treatment is highly specific to the patient; the endogenous cells provide a higher degree of safety, as they will not interfere with other cellular and metabolic processes.

The researchers have created a treatment platform called E-SYNC, allowing them to control the activity of CAR-T cells by adding an “on” and “off” switch using SynNotch technology.

“A synNotch receptor that recognizes a specific priming antigen […] can be used to locally induce expression of a CAR,” the article, published in PubMed, reads.

Because some healthy cells in the body exhibit certain markers or proteins that are similar to those found in tumor cells, having the CAR-T cells act on all of these cells would damage healthy, viable cells. Instead, Okada and Lim inject the cells while they’re in an “off” state. When they are close to a target tumor cell, E-SYNC activates the cell, initiating an attack on the tumor cell. After the attack, the CAR-T cell is deactivated to protect healthy cells from being attacked until it is near another tumor cell.

Laura López González, a science correspondent from UCSF, commented on the impact and applications of this new research.

“All of this, we hope, will make E-SYNC more effective than traditional CAR-T therapy and with less side effects,” González said. “I think there’s a reasonable chance we can apply similar approaches to other cancers, like HER2-positive breast cancer.”

Written by: Naren Krishna Jegan — science@theaggie.org