Checkpoint Inhibitors

A significant challenge in cancer immunotherapy is that cancers typically employ strategies to suppress and evade the immune system.  One of the key strategies used is the hijacking of immune checkpoint pathways by cancer. Immune checkpoints are a regulatory mechanism that the immune system uses to modulate the size and duration of an immune response to a foreign challenge. Checkpoint pathways are regulated by ligand/receptor interactions.  A ligand can be thought of as a key, whilst the receptor is the lock.  Cancer cells may express high numbers of ligand molecules on their surface in order to interact with the receptors on cells of the immune system applying a brake to their anti-cancer activity. These ligand/receptor interactions may be targeted by the use of blocking monoclonal antibodies (called checkpoint inhibitors) aimed at either the key (ligand) or the lock (receptor) to prevent their interaction. Thus either checkpoint strategy releases the “brake” on the immune system to enhance a response against cancer. 

Amongst the checkpoint inhibitors in development or on the market, anti-PD-1 has attracted the most attention. The PD-1 (programmed death-1) receptor is expressed on T cells and pro-B cells (immune cells).  PD-1 and its ligands, PD-L1 and PD-L2, play an important role in down-regulating the immune system by preventing the activation of T-cells and inhibiting T cell proliferation. The PD-L1 ligand is expressed by non-lymphoid tissues as well as by activated antigen presenting cells (APCs). PD-L1 is a protein frequently overexpressed on the surface of cancer cells that acts as a disguise, allowing cancer cells to hide from the immune system.  When the anti-PD-1 antibody attaches to the PD-1 receptors on immune cells, the cancer can no longer hide from the patient’s immune system, allowing the body’s T-cells to fight the cancer.  An alternative approach is to use an antibody to the anti-PD-L1 ligand on the cancer cell, similarly blocking the interaction of the ligand with the receptor. Antibodies to checkpoints other than PD-1 are also marketed or in development. We plan to evaluate which checkpoint inhibitor would be the best partner for our vaccine.