As mentioned in the previous section, some agents are targeted to immune checkpoints, where they influence the immune response; these are known as checkpoint inhibitors. There are several different types of checkpoint inhibitors.
Immune checkpoints are molecules that regulate the activity of the immune system. While multiple drug forms have the potential to be checkpoint inhibitors, the first generation that are most well-known are monoclonal antibodies used to disable a cancer cell’s method of evading the immune system. A checkpoint is a protein on an immune cell that must be either activated or inactivated before an immune response can be elicited. Cancer cells can often escape detection by interfering with checkpoints. Checkpoint inhibitors work by modifying the activity of these checkpoints, commonly by inhibiting their regulatory activity, thus enabling the immune system to recognize and attack cancer cells.
Robert Andtbacka, MD, explains the different types of checkpoint inhibitors and how they function.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a checkpoint protein expressed on T cells. The protein acts as a negative T-cell regulator on immune activation and is meant to prevent T cells from attacking other cells, notably healthy self-cells. The function of CTLA-4 may also include regulation of regulatory T cells that dampen immunity. Inhibition of the CTLA-4 checkpoint therefore increases the immune response, allowing T cells to attack cancer cells that otherwise may have gone unrecognized by the immune system (see Figure 2).
Like CTLA-4, programmed death-1 (PD-1) is a checkpoint receptor that functions as a negative T-cell regulator. PD-1 is a receptor for programmed death ligand-1 (PD-L1), which is expressed on the surface of healthy self-cells and prevents T cells from killing those cells. However, some cancer cells also express PD-L1, and this allows them to escape the immune response. Monoclonal antibodies have been developed to bind PD-1, preventing the deactivation of the T-cell response (see Figure 2).
Monoclonal antibodies have also been developed to bind and inhibit PD-L1, allowing tumor cells to be recognized and destroyed by the immune system (Figure 2). In most cancer types, expression of PD-L1 is induced by the presence of immune cells in the tumor microenvironment. In some systems, PD-L1 is expressed constitutively by genomic changes. To date, there has been little observed difference between targeting PD-1 and PD-L1.
Figure 2. CTLA-4 and PD pathways.