Cancer immunotherapy is a treatment that uses the body’s own immune system to control and eliminate cancer. One major type of this therapy involves drugs known as checkpoint inhibitors. These treatments do not target the tumor directly but instead work by enabling the immune system to more effectively recognize and attack cancer cells. The approach has become a foundational treatment for many kinds of cancer.
The Immune System’s Role in Cancer Treatment
The immune system continuously patrols the body to identify and destroy foreign invaders and abnormal cells, including those that are cancerous. A type of white blood cell known as a T-cell is central to this surveillance process. T-cells are capable of recognizing specific proteins on the surface of abnormal cells and initiating a response to eliminate them.
To maintain balance and prevent the immune system from becoming overactive and attacking healthy tissues, the body has safety mechanisms called immune checkpoints. These checkpoints are proteins on the surface of immune cells that act like “brakes” or “off-switches.” When T-cells receive a checkpoint signal, their aggressive activity is dampened, which is a normal process for maintaining self-tolerance.
Some cancer cells have developed the ability to exploit these safety mechanisms. These malignant cells can produce high levels of specific proteins on their surface that bind to the checkpoint receptors on T-cells. This interaction sends a “stop” signal to the T-cells, tricking them into ignoring the cancer and allowing it to grow unattacked.
How Checkpoint Inhibitors Work
Checkpoint inhibitors are therapeutic antibodies designed to disrupt the deceptive signals that cancer cells send to the immune system. They function by physically blocking the connection between checkpoint proteins on T-cells and the partner proteins on tumor cells. This action “releases the brakes” on the immune system, restoring the ability of T-cells to recognize, target, and destroy cancerous cells.
One of the first and most well-understood checkpoint pathways involves a protein on T-cells called CTLA-4. When T-cells are activated, CTLA-4 appears on their surface and works to tone down the immune response. Drugs like ipilimumab are designed to block CTLA-4, preventing it from turning off the T-cell response and thereby sustaining a more powerful and prolonged attack against tumor cells.
Another prominent checkpoint pathway involves the PD-1 receptor on T-cells and its partner protein, PD-L1, which is often found in high amounts on the surface of various cancer cells. The binding of PD-L1 to PD-1 suppresses T-cell activity. Checkpoint inhibitor drugs, including pembrolizumab and nivolumab, work by blocking the PD-1 receptor, while others like atezolizumab block the PD-L1 protein. Both approaches prevent the “off” signal from being delivered, allowing T-cells to proceed with their anti-cancer functions.
By targeting these distinct but complementary pathways, checkpoint inhibitors can unleash a potent immune response. Some treatments may even combine inhibitors that block different checkpoints, such as CTLA-4 and PD-1, to further enhance the immune system’s ability to fight cancer.
Cancers Treated with Checkpoint Inhibitors
The application of checkpoint inhibitors has expanded significantly and they are now used to treat a wide array of cancers. These therapies are often employed for cancers that are advanced, have spread, or have not responded to other treatments like chemotherapy. Common malignancies treated with these drugs include melanoma, non-small cell lung cancer, kidney cancer, and bladder cancer.
The list of cancers for which checkpoint inhibitors are approved continues to grow as research advances. Other examples include certain types of head and neck cancer, Hodgkin lymphoma, stomach cancer, liver cancer, and colorectal cancer. In some cases, these drugs are used in combination with other cancer treatments to improve outcomes.
Eligibility for treatment with a checkpoint inhibitor can depend on the tumor’s specific characteristics. For instance, doctors may test a patient’s tumor for certain biomarkers, such as high levels of the PD-L1 protein. A high expression of PD-L1 can indicate that a drug blocking the PD-1/PD-L1 interaction is more likely to be effective.
Potential Side Effects of Treatment
Because checkpoint inhibitors work by amplifying the immune system, their side effects differ from those associated with traditional chemotherapy. The adverse effects are a direct result of the newly activated immune system attacking healthy tissues and organs in addition to cancer cells. These complications are known as immune-related adverse events (irAEs) and can affect nearly any part of the body.
The side effects can range from mild to severe and often appear within the first few months of starting treatment, though they can occur at any time. The most frequently affected areas include the skin, which can lead to rashes or itching, and the gastrointestinal tract, causing conditions like colitis. Other common irAEs involve inflammation of the liver (hepatitis), lungs (pneumonitis), and endocrine glands like the thyroid.
The management of these side effects is a component of the treatment plan. Mild reactions may be managed with topical creams for skin rashes or other supportive care. For more serious inflammatory reactions, treatment often involves medications that suppress the immune system, such as corticosteroids. These drugs help to reduce the inflammation and control the overactive immune response.