Immune Checkpoint Inhibitor (ICI) therapy represents an advancement in cancer treatment, shifting focus from directly targeting cancer cells to empowering the body’s own defense mechanisms. It harnesses the immune system, which naturally identifies and eliminates abnormal cells, including cancer. By removing specific barriers that cancer cells exploit, ICI therapy allows the immune system to recognize and attack tumors more effectively. This strategy has redefined treatment for various cancers, offering hope for durable responses.
What is ICI Therapy?
ICI therapy, also known as immune checkpoint inhibitor therapy, is a type of immunotherapy that enhances the body’s natural immune response against cancer, unlike traditional treatments like chemotherapy or radiation that directly target cancer cells. It achieves this by focusing on “immune checkpoints,” which are molecules on immune cells that act as natural “brakes” to prevent the immune system from overreacting and harming healthy tissues.
Cancer cells can sometimes exploit these checkpoints, effectively “turning off” the immune cells that would otherwise attack them. This allows tumors to evade detection and destruction, growing and spreading. ICI therapy works to counteract this evasion by blocking these “off” signals, thereby “releasing the brakes” on the immune system. This allows immune cells, particularly T cells, to recognize and attack cancer cells.
How ICI Therapy Works
The core mechanism of ICI therapy involves blocking specific proteins on immune cells or cancer cells that normally dampen the immune response. Two prominent examples of these immune checkpoints are Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4). These proteins act as regulatory switches, ensuring that immune responses are not excessively strong, which could otherwise lead to autoimmune reactions.
Cancer cells often express high levels of proteins that bind to these checkpoints, such as PD-L1 (Programmed Death-Ligand 1), which binds to PD-1 on T cells. When PD-L1 on a tumor cell connects with PD-1 on a T cell, it sends an “off” signal, preventing the T cell from attacking the cancer. ICI drugs, such as pembrolizumab and nivolumab, are designed to block the interaction between PD-1 and PD-L1, effectively disarming this “off” switch. This blockade reactivates the T cells, allowing them to recognize and eliminate the tumor cells.
A different pathway involves CTLA-4, which is primarily found on the surface of T cells and helps regulate their initial activation. CTLA-4 competes with another molecule, CD28, for binding to proteins called B7-1 and B7-2 on other cells. When CTLA-4 binds to B7 proteins, it delivers an inhibitory signal, dampening the T cell’s activity. Ipilimumab is an ICI drug that blocks CTLA-4, preventing this inhibitory signal and promoting T cell activation and proliferation, particularly in the lymph nodes. By targeting these distinct checkpoints, ICI therapies restore the immune system’s ability to mount an effective anti-tumor response.
Cancers Treated with ICI Therapy
ICI therapy has expanded the treatment landscape for numerous cancer types, benefiting many patients. The U.S. Food and Drug Administration (FDA) has approved various ICI drugs for a growing list of malignancies. These therapies are used as single agents or in combination with other treatments, such as chemotherapy, for approximately 50 cancer types.
Melanoma, a severe form of skin cancer, was among the first cancers to respond well to ICI therapy. Drugs like ipilimumab, nivolumab, and pembrolizumab have improved outcomes for patients with advanced melanoma. Non-small cell lung cancer (NSCLC) is another area where ICIs have shown success, with drugs like nivolumab, pembrolizumab, atezolizumab, and durvalumab being approved for various stages of the disease.
Beyond melanoma and lung cancer, ICI therapy is also used in the treatment of:
- Kidney cancer (renal cell carcinoma)
- Bladder cancer
- Hodgkin lymphoma
- Head and neck squamous cell cancers
- Liver cancer
- Stomach cancer
- Cervical cancer
- Certain types of colorectal cancer, particularly those with specific genetic characteristics
Ongoing research continues to broaden the application of these therapies, with clinical trials exploring their use in additional cancer types and combinations.
Potential Side Effects and Their Management
While ICI therapy offers promising outcomes, it can lead to unique side effects, known as immune-related adverse events (irAEs), which differ from those seen with traditional chemotherapy. These adverse events arise because the immune system, now disinhibited, can sometimes mistakenly attack healthy tissues throughout the body. The severity of irAEs can range from mild to severe, and they can affect nearly any organ system.
Common irAEs include:
- Skin reactions like rashes and itching
- Gastrointestinal issues such as colitis (inflammation of the colon) leading to diarrhea and abdominal pain
- Inflammation of endocrine glands, which can affect hormone production
- Lungs (pneumonitis)
- Liver (hepatitis)
- Kidneys (nephritis)
- Muscles or joints (myositis, arthritis)
These toxicities can manifest during treatment or even months after therapy.
Managing irAEs typically involves a multi-step approach based on their severity. For mild (Grade 1) symptoms, treatment may continue with close monitoring, except for certain neurological, hematological, or cardiac toxicities. Moderate (Grade 2) irAEs usually require temporarily stopping ICI therapy and initiating corticosteroids, which are anti-inflammatory medications. For severe (Grade 3 or 4) irAEs, high-dose corticosteroids are generally administered, and the ICI therapy may be permanently discontinued. If corticosteroids are ineffective, other immunosuppressive medications may be considered to control the immune response.