The importance of co-stimulation

Normal T cell co-stimulation. To prevent inappropriate T cell activation, T cells need a second signal that permits T cell activation and killing. Signal 2 is provided by the interaction between co-stimulatory molecules expressed on the antigen-presenting cell and the T cell (Figure 1.5a)When cells are infected, they increase the amount of co-stimulatory molecules that bind to co-stimulatory receptors on T cells. Conversely, TCR binding in the absence of co-stimulation switches T cells off (anergy) or causes them to die. This mechanism protects the body against inappropriate T cell activation and autoimmunity. 

To evade immune detection, cancer cells often decrease the amount of co-stimulatory molecules, increasing instead the amount of molecules that do the opposite and act as checkpoints. Targeting these processes with antibodies that block immune checkpoints has met with considerable clinical success and these treatments are now in routine clinical practice for some cancers. 

CAR-T cell co-stimulation. To overcome the need for signal 2 from cancer cells that are adapted not to supply it, second-generation CAR-T cells incorporate a co-stimulatory molecule into the CAR construct (see Figure 1.4b). This avoids the need to introduce additional genes or drugs to provide signal 2. Instead, TCR–antigen binding delivers both signal 1 and signal 2, thus circumventing the need for separate co-stimulation (Figure 1.5b). This greatly increases CAR-T cell efficacy and persistence. 

There are numerous co-stimulatory molecules, but the ones that are relevant for current CAR-T cell technologies are CD28 and 4-1BB (also known as CD137). By incorporating these co-stimulatory molecules into the CAR construct, second-generation CAR-T cells can independently recognise antigens, become activated, kill, self-replicate and persist. 

Figure 1.5 (a) Physiological co-stimulation. To prevent inappropriate T cell activation, a second signal is provided by the interaction between co-stimulatory molecules expressed on the antigen-presenting cell and the T cell. (b) In second-generation chimeric antigen receptor (CAR) T cells, the second signal is provided by a co-stimulatory molecule (CD28 or 4-1BB) incorporated into the CAR construct, thereby activating the CAR-T cell against the tumour cell. MHC, major histocompatibility complex; TCR, T cell receptor.