Checkpoint Inhibitors: How a New Class of Cancer Drug Works

Checkpoint inhibitors have fundamentally changed cancer treatment over the past fifteen years. Pembrolizumab is one of the most widely used drugs in this class, but understanding why it works requires understanding the broader biology of immune checkpoints. Here is a plain-English explanation.

What is an immune checkpoint?

The immune system is powerful, and if left entirely unchecked it would attack healthy tissue as well as pathogens and abnormal cells. Immune checkpoints are molecular brakes - proteins that regulate immune activity to prevent autoimmune damage. They are a necessary part of normal immune function. The problem arises when tumours exploit them.

An immune checkpoint is essentially a receptor-ligand pair. The receptor sits on the surface of an immune cell (typically a T cell); the ligand is expressed on another cell. When the receptor binds its ligand, an inhibitory signal is delivered: slow down, stand down, do not attack. Tumours that express checkpoint ligands can exploit this mechanism to suppress the immune response directed at them.

CTLA-4 and PD-1: the two main targets

Two checkpoints have been most successfully targeted by approved drugs:

• CTLA-4: Expressed on T cells; its ligands (B7-1 and B7-2) are found on antigen-presenting cells. CTLA-4 dampens early T cell activation. Ipilimumab (Yervoy) is the main approved drug targeting CTLA-4. It was the first checkpoint inhibitor approved for cancer treatment, in melanoma.
• PD-1: Expressed on activated T cells; its ligands are PD-L1 and PD-L2. PD-1 regulates immune activity in peripheral tissues - including within tumours. Pembrolizumab and nivolumab are PD-1 inhibitors. PD-L1 is also targeted directly by drugs such as atezolizumab and durvalumab.

Pembrolizumab binds to PD-1 on T cells, preventing PD-L1 on tumour cells from delivering its inhibitory signal. The result is a more sustained and effective immune response against the tumour.

Combination checkpoint blockade

CTLA-4 and PD-1 act at different stages of the immune response. Combining drugs targeting both pathways - nivolumab plus ipilimumab, for example - can produce higher response rates than either drug alone, at the cost of a higher incidence of immune side effects. Combinations are used in melanoma, NSCLC, and other tumour types where the increased activity is judged to outweigh the added toxicity risk.

Where pembrolizumab sits in this landscape

Among checkpoint inhibitors, pembrolizumab is the most widely approved - covering more tumour types than any other single agent in this class. Its PD-1 targeting mechanism, extensive evidence base from the KEYNOTE programme, and the availability of the subcutaneous formulation make it the most frequently used checkpoint inhibitor for home-based administration.