The immune system works to protect a person from illness by fighting foreign invaders like viruses and bacteria. It can also recognize harmful changes happening inside the body, like the formation of cancer.
Sometimes the immune system is not able to make the distinction between healthy and cancerous cells, and fail to recognize a cancer. Other times, it may mistakenly start attacking normal cells, leading to what is called an autoimmune disease.
To manage system reactions, “immune checkpoints” are utilized. These checkpoints are molecules found on certain immune cells, called T-cells, that need to be activated or, in some cases, inactivated for a proper immune response to be initiated.
Cancer cells can evade being targeted by T-cells by displaying proteins that are normally found on healthy cells. When this happens, T-cells are unable to identify cancer cells and take action against them.
How immune checkpoint inhibitors work
Immune checkpoint inhibitors correct how detection-evading cancer cells and T-cells interact so that T-cells can recognize tumor cells and mount an appropriate immune response against them.
Immune checkpoint inhibitors that have been developed to date typically target one of two different proteins that play a major role in the identification of cancerous cells: programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
PD-1
PD-1 is an immune checkpoint protein that is located on the surface of T-cells. Normal cells have a protein called programmed cell death ligand 1 (PD-L1), which binds to the PD-1 protein on T-cells to “turn off” any immune reaction so as to prevent T-cells from damaging or killing them. But cancer cells can also be covered with PD-L1 proteins to camouflage themselves as healthy cells and thwart an immune response.
Monoclonal antibodies can be used to prevent the binding of cancer cells to T-cells via the PD-1 protein. One way this is done is by blocking the PD-1 protein on T-cells, using approved treatments such as Keytruda (pembrolizumab) or Opdivo (nivolumab). A number of PD-1 monoclonal antibodies are also in development and testing, like AGEN 2034, BGB-A317, BI-754091, CBT-501 (genolimzumab), MEDI0680, MGA012, PDR001, PF-06801591, REGN2810 (SAR439684), and TSR-042.
A second way by which PD-1 immune checkpoint inhibitors can work is by blocking the PD-L1 on cancer cells. Such PD-L1 inhibitors include approved therapies like Imfinzi (durvalumab), Tecentriq (atezolizumab), and Bavencio (avelumab), and investigative ones like CX-072.
PD-1 and PD-L1 inhibitory therapies have shown considerable promise in treating solid tumors. One troubling side effect, however, is that they can cause T-cells to attack healthy cells as well. Lesser side effects are often associated with such symptoms as fatigue, cough, nausea, loss of appetite, and skin irritation. More severe ones can affect the lungs, intestines, liver, and kidneys.
CTLA-4
CTLA-4, similar to PD-1, is an immune checkpoint protein that acts as an “off switch” in regulating the immune response. The CTLA-4 inhibitor Yervoy (ipilimumab) is an approved checkpoint immunotherapy for people with metastatic melanoma, and is currently being tested to treat other types of cancer. Side effects to Yervoy are also possible for the same reason as other checkpoint immunotherapies: they stop the work of T-cells in protecting the body. Common side effects of Yervoy can include tiredness, diarrhea, itching, rash, nausea, fever, and difficulty falling or staying asleep. More severe side effects may also occur and more frequency so compared to compared to treatments that target PD-1 or PD-L1, when using this checkpoint inhibitor
AGEN 1884 is a CTLA-4 inhibitor that is currently being tested in clinical trials.
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