Researchers in Lausanne, Switzerland, have engineered a novel chimeric antigen receptor (CAR)-T cell therapy that can be remotely controlled using readily available oral drugs. This innovative approach introduces an on/off switch, potentially enhancing the safety and efficacy of CAR-T cell therapy, especially for solid tumors.
Addressing CAR-T Challenges in Solid Tumors
CAR-T cell therapies have shown success in treating advanced liquid cancers like leukemia and lymphoma. However, their application to solid tumors, such as breast, lung, and prostate cancer, has been challenging. According to Melita Irving, PhD, a researcher at the Ludwig Institute for Cancer Research, Lausanne, solid tumors pose significant challenges to CAR-T therapy in terms of both safety and efficacy. The new design directly addresses these issues by incorporating on/off switches engaged by drugs already approved and in clinical use.
Engineering the On/Off Switch
The study, published in PNAS, details how the engineered CAR-T cell therapy can be activated by venetoclax and deactivated by lenalidomide within hours. Venetoclax activates the anti-cancer activity of the receptor, enabling it to target cancer cells, while lenalidomide marks the cell for disposal by the body's waste disposal system.
Potential for Improved Safety and Durability
Greta Maria Paola Giordano Attianese, PhD, from the Ludwig Institute, emphasized the potential for improved safety. "Having the ability to remotely switch CAR-T cells on to varying degrees using different doses of an activating drug—and then off on demand, as needed—would improve the safety of this therapy," she said. Furthermore, remote control of CAR-T cell activity could mitigate T cell exhaustion, potentially improving the durability of patient responses.
Future Directions
While the therapy is currently in preclinical stages, the research team plans to advance it further and assess its ability to improve the performance of existing CAR-T cell therapies. The focus will be on determining if the on/off switch mechanism can indeed enhance the safety and efficacy of CAR-T cell therapy, particularly in the challenging landscape of solid tumor treatment.
