Immune checkpoint blockade represents a significant advancement in cancer treatment. This therapeutic strategy harnesses the body’s own immune system to identify and eliminate cancer cells. By removing specific “brakes” on immune responses, these treatments enable immune cells to effectively target and destroy malignant cells. This method empowers the body’s natural defenses rather than directly attacking cancer cells.
The Immune System and Its Checkpoints
The human immune system constantly works to protect the body from foreign invaders like bacteria and viruses, and from internal threats such as abnormal cells. Specialized immune cells, particularly T-cells, are designed to recognize and destroy unhealthy or cancerous cells.
To prevent the immune system from attacking healthy tissues, the body employs regulatory mechanisms known as immune checkpoints. These checkpoints act like natural “brakes” or “off switches” on immune cell activity. Proteins on the surface of immune cells interact with partner proteins on other cells, sending signals that can either activate or deactivate the immune response. These control points are crucial for maintaining immune balance and preventing autoimmune conditions.
How Cancer Exploits Immune Checkpoints
Cancer cells have developed strategies to evade detection and destruction by the immune system. They hijack immune checkpoints designed to protect healthy cells. Cancer cells can express high levels of specific proteins, such as programmed death-ligand 1 (PD-L1).
When PD-L1 on a cancer cell binds to its corresponding receptor, programmed death-1 (PD-1), on a T-cell, it sends an inhibitory signal. This interaction “turns off” the T-cell, preventing it from recognizing and attacking the cancer cell. Other checkpoint pathways, like the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway, can also be manipulated by cancer cells to suppress immune activity. This immune evasion allows cancer cells to grow and spread unchecked, forming tumors and metastasizing throughout the body.
Immune Checkpoint Blockade: A New Approach to Cancer Treatment
Immune checkpoint blockade therapies are designed to counteract cancer’s immune evasion tactics by “releasing the brakes” on the immune system. These treatments involve administering specific antibodies that target and block the interactions between checkpoint proteins. For instance, an antibody might bind to PD-1 on T-cells, preventing PD-L1 on cancer cells from deactivating them.
Alternatively, an antibody could bind directly to PD-L1 on cancer cells, stopping it from engaging with PD-1 on T-cells. By blocking these inhibitory signals, the T-cells remain active and are re-enabled to recognize and attack the cancerous cells. This approach empowers the patient’s own immune system to mount a robust and sustained anti-tumor response, leading to tumor shrinkage and prolonged survival in many patients.
Types of Immune Checkpoint Inhibitors and Their Use
Immune checkpoint inhibitors fall into main classes, each targeting a specific checkpoint pathway. PD-1 inhibitors block the PD-1 receptor on T-cells, preventing cancer cells from deactivating them. PD-L1 inhibitors target the PD-L1 protein directly on cancer cells, preventing its interaction with PD-1.
Another class includes CTLA-4 inhibitors, which block the CTLA-4 protein. Blocking CTLA-4 can enhance the initial activation and proliferation of T-cells. These therapies are administered intravenously, typically over a period of 30 to 90 minutes, at regular intervals such as every two, three, or four weeks. They are approved for treating various advanced cancers, including melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, and certain types of head and neck cancers. Their application continues to expand as research identifies new indications and combinations.
Managing Treatment and Side Effects
Immune checkpoint blockade therapies can cause unique side effects known as immune-related adverse events (irAEs). These side effects occur because, with the “brakes” released, the re-activated immune system can mistakenly attack healthy tissues in addition to cancer cells. These reactions differ from side effects commonly associated with traditional chemotherapy.
Common irAEs include skin rashes, fatigue, and inflammation of various organs such as the colon (colitis), lungs (pneumonitis), liver (hepatitis), or endocrine glands (e.g., thyroiditis). Close monitoring by a healthcare team is important throughout treatment. If irAEs develop, they are often managed with corticosteroids to suppress the immune response, or with other immunosuppressive medications, allowing patients to continue their cancer treatment.