Researchers Advance CAR T-Cell Safety with Remote Control and Risk Prediction Studies

Researchers have developed a CAR T-cell that can be swiftly switched off on demand using venetoclax, a cancer drug already in clinical use. The team, led by researchers at Ludwig Lausanne and the École Polytechnique Fédérale de Lausanne (EPFL), reported in the current issue of Nature Chemical Biology the design and preclinical evaluation of these new CAR-T cells, demonstrating both their efficacy and controllability in mouse models of cancer.

The new remote-controlled CAR-T cell sports a "drug-regulated off-switch PPI CAR" (DROP-CAR) that places the switch on the outside of the cell. The signaling component of the CAR inside the cell is linked to a strip of protein on the outside of the cell. That strip carries at its tip a computationally designed human domain known as dmLD3 that binds a protein named BCL-2 with very high affinity. The cancer-sensing antibody of the CAR carries at its tail end the bit of BCL-2 recognized by dmLD3.

Held together by this spontaneous protein-protein interaction, the CAR remains intact and functional until venetoclax disrupts that interaction. At that point, the dmLD3 and BCL-2 domains disengage and the CAR falls apart, switching off CAR-T cell's lights. When venetoclax is withdrawn, the CAR reassembles and the CAR-T cells get back to killing cancer cells.

The remote control doesn't trigger the self-destruction of the CAR-T cells, which is how many others have approached this challenge, but simply prompts them to disengage and fall off from their cancerous targets. Unlike previous controllable CAR designs, the system uses only human protein components and a clinically approved, non-immunosuppressive drug to directly disrupt tumor cell binding by the CAR-T cells.

This ability to control CAR-T cell activity could also help mitigate a phenomenon known as T cell "exhaustion" that accounts for the failure of many T cell-based immunotherapies. Caused by the continuous and nonproductive stimulation of T cells in the immunosuppressive microenvironment of tumors, exhaustion pushes T cells into a functionally sluggish state in which they're incapable of killing their target cells. Previous studies have shown that giving CAR-T cells periods of rest between bouts of active tumor targeting can reverse the genomic alterations that drive exhaustion and boost their functional efficacy.

Separately, a team at Children's Hospital Los Angeles is conducting a first-of-its-kind prospective study to identify brain and biologic markers that may help predict risk for immune effector cell–associated neurotoxicity syndrome (ICANS) in pediatric patients. Funded by a $4.5 million grant from the National Institutes of Health, the study aims to address a critical gap in predicting which children will experience this serious complication.

ICANS affects 30% to 50% of pediatric patients treated with CAR T-cell therapy and can cause headaches, confusion, seizures, and—in rare cases—brain swelling and death. While most patients achieve remission with CAR T-cell therapy for acute lymphoblastic leukemia (ALL), clinicians can't predict which children will experience neurotoxicity.

One unique aspect of the study is that it's prospective, with the team following patients before, during, and after CAR T-cell therapy. That design allows researchers to track how the brain and immune system change over time and to identify biomarkers that may help predict if a child is likely to develop ICANS. Most prior studies have been retrospective, looking back after neurotoxicity has already occurred.

Now halfway through the five-year study, the team has enrolled nearly 50 patients, along with 20 healthy controls. The researchers are also preparing to expand the study to two additional local institutions.

The team's early data suggest that children with pre-existing brain damage—possibly from prior treatments, including chemotherapy, and ongoing illness—may be most vulnerable to developing ICANS. While these findings are preliminary, they reinforce the importance of collecting detailed brain data before CAR T-cell therapy begins.

To better understand these vulnerabilities, the researchers are using advanced brain MRI methods alongside biologic data collected from cerebrospinal fluid and blood. One area of focus is whether the blood–brain barrier—the protective layer that helps regulate what enters the brain—is disrupted in children who go on to develop neurotoxicity.

Importantly, the study is designed to follow children long-term. Even after ICANS resolves clinically, the team will continue to monitor patients to better understand whether there are lasting effects on brain development, cognition, or function.