A primary function of the immune system is to determine which cells or substances are self or non-self (see Overview, page 1). The immune system only makes enough white blood cells to fight non-self cells, also called antigens, present in the body. When the immune system is alerted to the threat of antigens, such as bacteria or viruses, it ramps up production of T-cells that attack and destroy the antigens. After an attack, the immune system must slow down so that the T-cells don’t begin attacking healthy cells. It does this through the use of checkpoints.
Checkpoints keep the immune system “in check.” This process happens between proteins and receptors at the cellular level. To understand how this occurs, it’s important to know that the surface of each cell is not completely round and smooth. Cells are covered with receptors and proteins, which work like puzzle pieces. Proteins have “tabs” that stick out, and receptors have “spaces” that curve inward. When the puzzle pieces fit together (known as binding), chemical signals and information are exchanged in a biochemical reaction; this process allows cells to communicate with each other. When the correct proteins and receptors connect, a series of signals is sent to the immune system to slow down once an immune response is finished.
The immune system also can attack and kill cancer cells. In order for a cancer to grow, it must turn off the immune response. This occurs when cancer cells express immune checkpoint proteins. Three checkpoint receptors that slow down the immune system have been identified, and two are present in lung cancer. When they combine, the reaction signals it’s time to slow down.
- PD-1 is a receptor involved with telling T-cells to die and to reduce the death of regulatory T-cells, which slow down the immune system after an immune response and inhibit T-cells that attack normal, healthy cells that weren’t eliminated before leaving the thymus. PD-1 can tell the immune system to slow down only if it connects with PD-L1.
- PD-L1 is a protein that, when combined with PD-1, sends a signal to reduce the production of T-cells and enable more T-cells to die.
The goal of immune checkpoint inhibitors is to prevent PD-1 and PD-L1 from connecting so that the immune system does not slow down. Checkpoint inhibitor drugs prevent these connections by targeting and blocking PD-1 or PD-L1, and the immune cells continue fighting the cancer. If either checkpoint is blocked, the immune system will not slow down and T-cells can continue to attack antigens and cancer cells.
However, cancer is smart and tries to hide from the immune system. One of the ways a cancer cell can outsmart the immune system is by producing PD-L1 on its own surface and using it as camouflage so that T-cells will see it as a normal cell. T-cells expect only normal cells to produce PD-L1, so when a T-cell encounters PD-L1 on a cancer cell, it is tricked into signaling the immune system to slow down. When an immune checkpoint inhibitor is given, it’s as if the immune system develops X-ray vision and sees through the cancer cell’s camouflage. This keeps the immune response from slowing down and also helps the immune system recognize cancer cells as foreign cells.
Although cancer cells can be clever, the immune system has a long memory when it comes to battling dangerous cells. When your immune system encounters a virus, such as chickenpox, the memory T-cells check to see if that virus has any characteristics of cells they have attacked in the past. If so, your memory T-cells offer you immunity from that virus, and most of the time you don’t get chickenpox again. The memory T-cells
alert the rest of the immune system, telling it to make more immune cells to attack the virus and keep you from getting the disease again. Memory T-cells stay alive and store this information for a long time, remaining effective long after treatment ends. Investigators believe that effective immunotherapy can result in cancer-specific memory cells that provide long-term protection against cancer.
Illustration: Immune Checkpoint Inhibitors (filename: Treatment Immune Checkpoint Inhibitor)
FDA-APPROVED IMMUNOTHERAPIES FOR LUNG CANCER
Immune checkpoint inhibitors
- atezolizumab (Tecentriq)
- durvalumab (Imfinzi)
- nivolumab (Opdivo)
- pembrolizumab (Keytruda)
As of 7/11/19
SIDEBAR: QUESTIONS TO ASK YOUR MEDICAL TEAM
- Would you recommend immunotherapy for my type of lung cancer?
- Why is immunotherapy the best treatment for me?
- Have you had success treating patients with immunotherapy?
- How will we determine what the goals of treatment will be?
- How will we know if it is working?
- Will I be able to receive other types of treatment if immunotherapy fails at some point?
- Will I still be able to work, travel and do regular activities during treatment?
- Should I consider a clinical trial?
- What are the side effects of the recommended treatment, and how are these managed?