Anti-CTLA4 antibodies are a type of immunotherapy that harnesses the body’s immune system to fight cancer. These antibodies specifically target CTLA-4, a protein that regulates immune responses. By modulating the immune system, anti-CTLA4 antibodies enhance the body’s ability to identify and eliminate cancer cells.
How Anti-CTLA4 Antibodies Work
The immune system uses “checkpoints” to regulate its activity. CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) is a protein on T-cells that acts as an inhibitory signal, or “brake.” When CTLA-4 binds to B7-1 (CD80) and B7-2 (CD86) on antigen-presenting cells, it dampens the T-cell response, preventing an overactive immune response.
Anti-CTLA4 antibodies, such as ipilimumab (Yervoy) and tremelimumab (Imjudo), are designed to block this inhibitory interaction. By binding to CTLA-4, these antibodies prevent CTLA-4 from attaching to its B7 ligands. This action “releases the brake” on T-cells, allowing them to become more active and proliferate. The increased activity of these T-cells enhances their ability to recognize and destroy cancer cells more effectively.
This mechanism boosts the T-cell response and can also deplete regulatory T-cells (Tregs) within tumors, which suppress anti-tumor immunity. Reducing Treg suppression and activating effector T-cells, anti-CTLA4 antibodies contribute to a stronger, more sustained anti-cancer immune response. This dual action helps the immune system overcome cancer’s evasion tactics.
Medical Applications
Anti-CTLA4 antibodies have shown effectiveness across several cancer types. Ipilimumab was initially approved for advanced melanoma, a severe skin cancer, and can induce long-term protection. This antibody is also used for certain colorectal cancers (MSI-H or dMMR), hepatocellular carcinoma (liver cancer), renal cell carcinoma (kidney cancer), and esophageal cancer.
These antibodies are frequently used in combination with other immunotherapies, most notably anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab), to enhance treatment effectiveness. The rationale behind combination therapy is to target different “immune checkpoints” simultaneously. While anti-CTLA4 antibodies primarily act by activating T-cells in the initial stages of an immune response, anti-PD-1 antibodies block a different pathway that tumors often exploit to suppress T-cell activity in the tumor microenvironment. This combined approach can lead to a more robust anti-tumor immune response, potentially improving patient outcomes.
Managing Treatment Effects
While effective, anti-CTLA4 antibody therapy can cause immune-related adverse events (irAEs) as the activated immune system may attack healthy tissues. These side effects can affect various organ systems, often appearing within the first 10 weeks. Common irAEs include skin reactions like rashes or itching.
Gastrointestinal issues are frequent, including diarrhea and colitis (inflammation of the colon). Endocrine glands, such as the thyroid or pituitary, can become inflamed, leading to conditions like hypothyroidism or hypophysitis. Endocrine symptoms like fatigue or headache can be non-specific, requiring prompt reporting to the healthcare team. Liver inflammation (hepatitis) is also a possible irAE, though less common.
Less frequently, anti-CTLA4 therapy can affect the nervous system or kidneys, or other rare immune-mediated conditions. Patients must immediately report any new or worsening symptoms to their healthcare provider, as early detection and management can mitigate severe outcomes. Management of irAEs often involves corticosteroids to suppress the immune response, and sometimes requires temporary interruption or permanent discontinuation.