Optimization of CAR-T Cell-Based Therapies Using Small-Molecule-Based Safety Switches

by Selleckchem | Sep 21 2023

Chimeric antigen receptor T cell therapy has demonstrated antileukemia efficacy. However, this therapeutic approach is hampered by severe cytokine release syndrome, which is a major impediment to its widespread application in the clinic. The safety of this approach can be improved by engineering a rapid and reversible "off" or "on" safety switch for CAR-T cells. Cutting-edge investigations combining the advantages of genetic engineering and chemical technology have led to the invention of small-molecule-based safety switches for CAR-T cells. Small molecules such as FITC, folate, rimiducid, rapamycin, proteolysis-targeting chimera (PROTAC) compounds, and dasatinib are being investigated to design such safety switches. Optimized CAR-T cells may have enhanced therapeutic efficiency with fewer adverse effects. Herein we summarize and classify current novel small-molecule-based safety switches for CAR-T cells that aim to provide pharmacological control over the activities and toxicities associated with CAR-T cell-based cancer immunotherapies.

Comments:

Chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in treating leukemia. However, one significant challenge is the occurrence of severe cytokine release syndrome (CRS), which limits its broader application in clinical settings. To address this issue, researchers have been exploring methods to engineer a safety switch for CAR-T cells, allowing for rapid and reversible control over their activity.

Cutting-edge investigations have combined genetic engineering and chemical technology to develop small-molecule-based safety switches for CAR-T cells. Several small molecules, including FITC, folate, rimiducid, rapamycin, proteolysis-targeting chimera (PROTAC) compounds, and dasatinib, are being investigated for their potential in designing such safety switches. These molecules offer the ability to modulate CAR-T cell activity and toxicity through pharmacological control.

The concept behind these safety switches is to incorporate a molecular mechanism that can be activated or deactivated by administering the corresponding small molecule. This enables precise control over CAR-T cell function, allowing clinicians to regulate the therapy's effects as needed. For example, the safety switch can be turned "off" to halt CAR-T cell activity in the event of severe adverse effects such as CRS, and then turned "on" again once the adverse effects have been managed.

The development of optimized CAR-T cells with small-molecule-based safety switches holds the potential to improve therapeutic efficiency while reducing adverse effects. By providing pharmacological control over CAR-T cell activities and toxicities, these safety switches offer a more tailored approach to cancer immunotherapy.

In summary, current research is focused on developing novel small-molecule-based safety switches for CAR-T cells. These switches aim to address the limitations of CAR-T cell therapy, particularly the severe cytokine release syndrome, by allowing for rapid and reversible control over CAR-T cell activity. The use of small molecules as safety switches provides a promising avenue for enhancing the therapeutic efficacy of CAR-T cell-based immunotherapies while minimizing adverse effects.