Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.
Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and boosts the body's immune response against cancer cells.
Ipilimumab was approved by the US Food and Drug Administration (FDA) in March 2011, for the treatment of melanoma, a type of skin cancer. It is undergoing clinical trials for the treatment of non-small cell lung carcinoma (NSCLC), small cell lung cancer (SCLC), bladder cancer and metastatic hormone-refractory prostate cancer.
The concept of using anti-CTLA4 antibodies to treat cancer was first developed by James P. Allison while he was director of the Cancer Research Laboratory at the University of California, Berkeley. Clinical development of anti-CTLA4 was initiated by Medarex, which was later acquired by Bristol-Myers Squibb. For his work in developing ipilimumab, Allison was awarded the Lasker Award in 2015. Allison later was the co-winner of the 2018 Nobel Prize in Physiology or Medicine.
Medical uses
Ipilimumab was approved by the U.S. Food and Drug Administration (FDA) in March 2011, to treat people with late-stage melanoma that has spread or cannot be removed by surgery. It was later approved by the US FDA on October 28, 2015, for stage 3 patients as adjuvant therapy. On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease." Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma in November 2012.
Nivolumab, in combination with ipilimumab is indicated for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma.
Ipilimumab, in combination with nivolumab, is indicated for the treatment of adults and adolescents twelve years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Ipilimumab, in combination with nivolumab, is indicated for the treatment of people with hepatocellular carcinoma who have been previously treated with sorafenib.
Ipilimumab, in combination with nivolumab, is indicated for the first-line treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test.
In October 2020, the U.S. FDA approved the combination of nivolumab with ipilimumab for the first-line treatment of adults with malignant pleural mesothelioma that cannot be removed by surgery. This is the first drug regimen approved for mesothelioma in sixteen years and the second FDA-approved systemic therapy for mesothelioma.
Adverse effects
A major drawback of ipilimumab therapy is its association with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation, occurring in ten to twenty percent of patients. Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems. A "risk evaluation and mitigation strategy" informs prescribers of the potential risks.
Between 5.7 and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis.
Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.
Interactions
The combination of ipilimumab with either leflunomide or vemurafenib may lead to increased hepatotoxicity.
Systemic corticosteroids should be avoided before starting ipilimumab; however, systemic corticosteroids may be used to treat an immune-related adverse reaction that arises from ipilimumab treatment.
Patients taking anticoagulants with ipilimumab should be monitored due to an increased risk of gastrointestinal bleeding.
Mechanism of action
T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.