Immune Checkpoint Inhibitors
Immune checkpoint inhibitors are a new class of drugs that are used to modulate the immune system to allow lymphocytes to attack the tumor cells resulting in tumor regression.
Targeting the immune system instead of the tumor means that these drugs can potentially be used to treat multiple tumor types. Another advantage of the immune checkpoint inhibitors is that they do not cause bone marrow suppression so they can be used in combination with many other agents (chemotherapy, vaccines, cytokines, etc.).
An immune checkpoint can either activate or inhibit the function of the T cell.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a “negative” regulator of T-cell response suppressing the T cell antitumor response. Ipilimumab is a fully human monoclonal antibody that blocks CTLA-4 enhancing the T cell response against tumors. This drug was FDA approved to treat metastatic melanoma as single agent or in combination therapy. Ipilimumab therapy resulted in durable responses and improvement and overall survival as single agent.
Another checkpoint of interest is the programmed death pathway that consists of PD1 (programmed death receptor 1) and PD-L1 (programmed death receptor ligand 1). The tumor cell puts a stop to the activation of PD1 and PD-L1. Once PD1 and PDL-1 are inhibited by the new immunomodulatory drugs, the T cell are able to recognize the cancer cells and fight them.
Nivolumab is the PD-1 inhibitor that was FDA approved for lung cancer.
This drug functions as a dual ligand inhibitor of PDL-1 and PDL2, in clinical trials it revealed efficacy in metastatic squamous cell lung cancer with 22% improvement in survival.
The most common side effects associated with this class of drugs are fatigue, shortness of breath, cough, nausea, and musculoskeletal pain. Less common but more serious side effects are immune mediated pneumonitis, colitis, hepatitis, nephritis and hypothyroidism.
Other checkpoint inhibitors currently being tested are pembrolizumab, atezolizumab, and avelumab.