Scientists at Ludwig Cancer Research have developed innovative chimeric antigen-receptor (CAR) T cells—an advanced cancer immunotherapy—that can be activated at varying intensities and switched off as needed using existing drugs. Led by Melita Irving and Greta Maria Paola Giordano Attianese from the Lausanne Branch of the Ludwig Institute, the design and preclinical testing of these CAR-T cells.
“CAR-T cells are currently effective against certain blood cancers, but they face challenges in treating solid tumors, particularly regarding safety and effectiveness,” said Irving. “We have addressed these issues by integrating on and off switches into the CAR design, which can be controlled by drugs that are already approved for clinical use. This could accelerate the progression of these remotely controlled CAR-T cells into clinical trials.
CAR-T cells are engineered to recognize specific antigens on cancer cells through synthetic receptors, triggering the T cells to destroy the targeted tumor cells. However, many solid tumor antigens also appear on healthy cells, which can lead to dangerous off-target effects. Furthermore, the immunosuppressive environment of solid tumors often causes T cells, including CAR-T cells, to become “exhausted,” weakening their anti-tumor capabilities.
“The ability to remotely adjust the activation of CAR-T cells using different doses of a drug—and then switch them off when necessary—would significantly enhance the safety of this therapy,” said Giordano Attianese. “Moreover, controlling CAR-T cell activity remotely could prevent T cell exhaustion, improving the long-term effectiveness of the treatment.”
As reported by newsgram, this concept builds on research from Ludwig Stanford’s Crystal Mackall, which demonstrated that giving CAR-T cells periodic rest intervals reprograms their gene expression, reverses exhaustion, and enhances their functionality.
Traditional CARs are single-chain receptors that link tumor antigen recognition directly to internal signaling components, which activate the T cells. The antigen-sensing part of the CAR typically comes from an antibody fragment designed to detect specific targets on tumor cells. The internal signaling components include CD3-ζ, necessary for activating the T cells, and a co-stimulatory protein that boosts the T cell’s function and longevity.
To enable more precise control, Irving, Giordano Attianese, and their team split the antigen-recognition and activation functions into two separate chains—the “receptor chain” and the “signaling chain.” With input from Bruno Correia of the École Polytechnique Fédérale de Lausanne (EPFL), they added a module that allows the two chains to be brought together using a drug called venetoclax. The drug serves as a bridge, linking the chains to form an active CAR complex, with the intensity of the response controlled by the drug dosage. This new CAR construct is termed the “inducible-ON” (iON) CAR.
To ensure safety, the team incorporated another drug-responsive component into the signaling chain, which reacts to the cancer drug lenalidomide. When lenalidomide binds to this component, it triggers the degradation of the CAR, effectively switching it off within 4-6 hours. This dual-function system, dubbed the iON/OFF CAR (iONØ-CAR), allows for precise control of CAR-T cell activity.
The researchers now plan to further study the performance of the iON and iONØ-CARs in various tumor models. They aim to determine whether remote control of the cells can prevent toxicity from overactive CAR-T responses and if intermittent rest periods can improve long-term tumor control.