Chimeric antigen-receptor (CAR) T cell therapies face two major challenges when deployed against solid tumors. First, many solid tumor antigens are also found at low levels on healthy cells, raising the risks of so-called “off-tumor, on-target” effects. Second, the immunosuppressive conditions of the solid tumor microenvironment can push CAR-T cells into a state of dysfunction known as “exhaustion”. A team led by Ludwig Lausanne’s Melita Irving and Greta Maria Paola Giordano Attianese reported in an October PNAS paper the design and evaluation of new types of CAR-T cells that could address both these challenges. Named “inducible-ON” (iON) CAR and iON/OFF CAR (iONØ-CAR), the cells can be switched on to varying degrees of intensity and then switched off on demand—to stem toxicity—using drugs that are already employed in the clinic. The iON CAR was made by separating the antigen-binding moiety of the CAR and the internal, signaling component of the construct that is required for T cell activation on two separate chains. The two chains were also engineered with an on-switch to enable the cancer drug venetoclax to draw them together and create an active CAR complex. The iONØ-CAR, meanwhile, was made by adding a second component to the signaling chain that is bound by another cancer drug, lenalidomide. That binding marks the chain for intracellular degradation to rapidly switch off CAR-T cell activity.
Dual ON/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs
PNAS, 2024 October 25