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An important feature of the immune cells in our bodies is their ability to distinguish between normal cells and those that are foreign, such as bacteria, or abnormal, such as cancer cells. This capability enables the immune system to attack and kill abnormal cells while leaving normal cells alone. To do this, the immune system uses “checkpoints” or molecules on immune cells that need to be turned on or off to start an immune response.
Cancer cells can sometimes use these checkpoints to avoid being attacked by the immune system. For example, cancer cells escape detection by producing molecules on their surface which bond with molecules on immune system cells. This tricks the immune system’s cells into thinking the cancer cells are healthy cells.
PD-1 is a checkpoint molecule on some immune cells. When PD-1 binds with another molecule on normal cells called PD-L1, it then acts as an off switch to keep immune cells from attaching to normal cells. When PD-1 binds with PD-L1, it instructs immune cells to leave healthy cells alone. But cancer cells can be tricky—some of them make extra PD-L1, which fools immune cells into recognizing the cancer cells as healthy cells and avoiding them.
Drugs that target these checkpoint molecules hold considerable promise as cancer treatments. Immunotherapy drugs called PD-1-/PD-L1-blocking antibodies effectively allow the patient’s immune system to find, unmask and destroy cancer cells.
Three PD-1-/PD-L1-blocking antibodies have been approved by the Federal Drug Administration (FDA):
These antibodies are approved as treatment for advanced melanoma. Pembrolizumab and nivolumab are also approved to treat head and neck cancer, urinary and bladder cancer, renal cell carcinoma, gastric cancer and Hodgkin’s lymphoma. They are also used to treat colon and rectal cancers that have a defect in a type of DNA repair that causes the cancer to have a genetic feature called “microsatellite instability-high (MSI-H).” MSI-H cancers are associated with Lynch syndrome, an inherited syndrome associated with colorectal, uterine and ovarian cancers.
Ongoing clinical trials are looking at using PD-1/PD-L1 blocking antibodies as immunotherapy for treating breast cancer and ovarian cancer. Many of these studies are evaluating immunotherapy in combination with other agents, including PARP inhibitors. Preliminary results are promising and suggest that targeted immunotherapy may be a new treatment for some ovarian and breast cancer subtypes. Importantly, a few early reports suggest that BRCA-mutated breast and ovarian cancers may also be sensitive to PD-1/PD-L1 inhibitors.
Although patients who are treated with check point inhibitors may receive substantial benefit, serious side effects associated with this type of immunotherapy can occur. Because immune checkpoint inhibitors change the way the immune system works, they can cause the immune system to attack both cancer and healthy cells. While side effects can occur in any organ, they are most commonly observed in the skin, digestive, liver and hormonal systems.
Common side effects of immune check point inhibitor include nausea or stomach pain; vomiting; loss of appetite; diarrhea; constipation; low sodium levels; abnormal liver function tests; itching or rash; fever; cough; shortness of breath; pain in muscles, bones or joints; and fatigue.
Less often, check point inhibitors can cause more serious problems in the lungs, eyes, kidneys, liver, pancreas, blood cells and nervous system. These include new or worsening cough, chest pain, shortness of breath, pale skin, easy bruising or bleeding, severe and ongoing muscle aches or weakness, joint pain, severe stomach pain, diarrhea and bloody stool, low levels of sodium in the body, confusion, slurred speech, loss of coordination and feeling unsteady.