Remotely controlled CAR-T cells: a safer and more flexible approach to cancer immunotherapy

A recent study published in Proceedings of the National Academy of Sciences (PNAS) introduces a new all-in-one ON/OFF-switch chimeric antigen receptor (CAR) design enabling the remote control of T cell activity with two clinically approved drugs, offering a safer and more flexible cancer immunotherapy approach.

This new study*, led by Greta Maria Paola Giordano Attianese and directed by Melita Irving, part of the Ludwig Institute for Cancer Research, Lausanne Branch at the University of Lausanne, addresses two major challenges in CAR-T therapy for solid tumors: safety and T-cell exhaustion. Their research on the development CARs that can be remotely switched on with the drug venetoclax and rapidly switched off with lenalidomide can allow clinicians the ability to modulate CAR-T cell therapy in patients.

Read the full <<article>>

CAR-T cells, which can recognize and robustly attack cancer cells, are highly effective and even curative against some liquid cancers, but can also cause severe side effects. The ability to control their activity remotely means that the therapy can now be adjusted or paused in patients, improving both safety as well as long-term efficacy by periodically resting the T cells. These new designs are particularly promising for the treatment of solid tumors, a major hurdle in current CAR-T therapies. Moreover, this all-in-one CAR design will be useful for testing against new targets in the clinic because if the side-effects are too severe the CAR-T cells can be stopped never to be active again by halting administration of venetoclax.

Several years ago, the team developed a computationally designed STOP-CAR, the first proof-of-principle for an off-switch CAR which could be reversibly disrupted by a small molecule. Although groundbreaking, the small molecule used was not approved for clinical use. In this new study, the team has gone a step further by designing both an ON-switch CAR and an all-in-one ON/OFF-switch CAR that can be remotely controlled using two clinically approved small molecules—venetoclax and lenalidomide—making the system more practical for clinical translation.

This technology could revolutionize cancer treatment by allowing clinicians to tailor CAR-T cell activity during therapy, improving patient safety and long-term treatment success.

This multi-institutional research, conducted in collaboration with the EPFL and led by Bruno Correia, is a significant step forward in making CAR-T therapy safer and more effective for solid tumor patients. The study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, and other key funding bodies.

* Dual ON/OFF- switch chimeric antigen receptor controlled by two clinically approved drugs.

• Recherche