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Immune Checkpoint Inhibitors

Immune checkpoint inhibitors stop the immune system from turning off before cancer is completely eliminated. They’re a type of immunotherapy.

The immune system relies on T cells to fight cancer. These specialized cells are extremely powerful and have the potential to damage healthy cells. T cell activity is controlled through “immune checkpoints,” which can be positive or negative. Positive immune checkpoints help T cells to continue their work, while negative immune checkpoints shut T cells off.

Immune checkpoints were discovered in 1995 by Jim Allison, Ph.D. Allison found that T cells are controlled by a safety mechanism or “brake” – a negative immune checkpoint protein called CTLA-4. This checkpoint protein shuts a T cell off to prevent it from accidentally damaging healthy cells. By blocking CTLA-4, Allison allowed T cells to continue working and eliminate cancer in a laboratory setting.

Allison’s work led to the development and approval of the first immune checkpoint inhibitor, ipilimumab, which blocks the immune checkpoint protein CTLA-4. Blocking CTLA-4 allows T cells to continue to do their work. Ipilimumab has extended the survival of patients with advanced melanoma.

A second negative immune checkpoint protein, PD-1, was identified in 2000. Pembrolizumab and nivolumab are immune checkpoint inhibitors that block PD-1. These drugs are used to treat several cancer types, including:

A third type of immune checkpoint inhibitor blocks PD-L1, which is a molecule that triggers the negative immune checkpoint PD-1. Atezolizumab, avelumab and durvalumab are immune checkpoint inhibitors that block PD-L1 and are used to treat several cancer types, including:

Each immune checkpoint inhibitor has distinct side effects. Moreover, not all types of cancer are currently treatable by this type of immunotherapy. A patient’s overall health and type of cancer determine which immune checkpoint inhibitors can be considered as treatment options.

MD Anderson offers many clinical trials investigating whether immune checkpoint inhibitors can be used to treat cancers other than the ones listed above. Many of these clinical trials are examining whether immune checkpoint inhibitors can be combined to enhance their effectiveness. MD Anderson is also studying the benefit of giving immune checkpoint inhibitors before or after other types of therapy, such as chemotherapy or surgery. Additionally, studies are underway to better understand why some patients respond to immune checkpoint inhibitors, but others do not.

Current immune checkpoint therapies target negative immune checkpoint proteins. MD Anderson is also investigating positive immune checkpoints, which also allow T cells to continue working. We’re leading several clinical trials examining the effectiveness of drugs that target positive immune checkpoints to sustain the cancer killing activity of T cells. Additionally, our researchers are identifying new positive immune checkpoint proteins and developing drugs that can be used to target them.