Multiple studies have recently and/or are presently investigating ipilimumab in combination with other drugs and follow-up survival rates in previously treated patients. It originally received FDA approval for malignant melanoma, including unresectable or metastatic melanoma. However, it has since received approval for several other malignancies, including renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, and researchers are investigating for many more, including several genitourinary tumors, rare pancreatic tumors, gallbladder tumors, etc. It is FDA approved for use in combination with nivolumab for advanced renal cell carcinoma, for previously treated microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) colorectal cancer, and, most recently, for hepatocellular carcinoma previously treated with sorafenib.
Ipilimumab is a CTLA-4 monoclonal antibody. Two signals are necessary for full T-cell activation: major histocompatibility complexes (MHC) I and II receptors on T-cells binding to tumor-associated antigens (TAA) presented by antigen-presenting cells (APCs) as well as CD28 receptor located on the T cell binding to CD80 and CD86 (B7 ligand subtypes) on APCs. These two signals result in T-cell proliferation and cytokine release, which triggers and amplifies the immune response. In response to this T-cell activation, cytotoxic T lymphocyte antigen-4 (CTLA-4) becomes upregulated, competing with CD28 for CD80 and CD86 binding on APCs. However, with a much higher affinity, it can downregulate the T cell activation, which results in a decreased immune response to TAAs. CTLA-4 is the primary negative regulator of T-cell-mediated antitumor immune responses and therefore represents a critical checkpoint for immunity, controlling both the intensity and duration of an immune response. Ipilimumab is an anti-CTLA-4 monoclonal antibody that prevents CD80 and CD86 on APCs from binding to CTLA-4 on T cells. This blockage of CTLA-4 signaling allows T-cell activation, proliferation, and amplification of T-cell-mediated immunity, which allows the patient's immune system to mount a better response.
Ipilimumab may only be administered in an intravenous (IV) manner, specifically with an IV line that contains a sterile, low protein binding filter in order to minimize protein medication loss. It should be infused over a period of 30 to 90 minutes. It should not be mixed or administered with any other medical products. No other specific or extra precautions are necessary.
Ipilimumab causes increased activation of T-cells, and thus its adverse effects generally are a result of excess T-cell activation. These immune-mediated reactions are very common, can affect any organ system, and are usually manageable. However, they can also manifest as serious, life-threatening complications. The most commonly affected systems include the gastrointestinal and integumentary systems, usually manifesting as a pruritic rash, diarrhea, or colitis. Other less commonly implicated systems include the hepatic, neurologic, ocular, and endocrine. Less common adverse effects include conjunctivitis, uveitis, inflammatory hepatitis, liver failure, hypothyroidism, hypopituitarism, adrenal insufficiency, hypogonadism, intestinal perforation, severe enterocolitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Ipilimumab currently has no contraindications. There have been no formal drug interaction studies conducted with ipilimumab. There have been no well-controlled studies in pregnant women, but ipilimumab is known to cross the placental barrier and be transmitted from the mother to the developing fetus. Therefore, use during pregnancy should only be a consideration if the potential benefits outweigh the potential risk to the fetus. It is unknown whether ipilimumab is secreted in human breast milk, but due to the risk of secretion and potential for adverse effects, use during nursing should once again only considered if the potential benefits outweigh the potential risks to the child. There have not been well-controlled studies in the pediatric population, but there are no current contraindications for usage in children.
Ipilimumab associated adverse events are generally manageable with supportive measures, including loperamide and/or diphenoxylate/atropine, and the occasional use of systemic corticosteroids. Most adverse effects are immune-related and occur within the first 12 weeks of initial treatment and resolve within the following 3 to 4 months. Severe adverse drug effects should also merit consideration as reasons to discontinue medical therapy with ipilimumab. The most common adverse effects are enterocolitis, including severe enterocolitis, moderate enterocolitis, and intestinal perforation, dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, or severe rash and hepatitis, including severe and moderate hepatotoxicity. More uncommon adverse effects include neuropathies, including peripheral neuropathy and Guillan-Barre syndrome, and endocrinopathies, including hypopituitarism, adrenal insufficiency, hypo and hyperthyroidism, hypogonadism, and Cushing syndrome. Adverse effects seen in less than 1% of patients included nephritis, pneumonitis, iritis, meningitis, pericarditis, uveitis, and hemolytic anemia. Effective monitoring of patients should include a thorough history and physical examination, including neurologic function and bowel habits, a complete dermatologic assessment, and baseline as well as serial monitoring of LFTs, endocrine panel, and TFTs.
Ipilimumab currently has no specific antidote for overdose of this drug. Therefore, careful monitoring of the administration of proper dosages and adverse effects is imperative. If severe adverse effects or rapid deterioration of the patient occur, the clinician should consider cessation of the drug.
Every member of the health care team is incredibly important in the management of patients receiving ipilimumab. At the level of the pharmacist, proper dosages of medications, as well as appropriate intervals between dosages, should be verified to ensure patient safety and avoid and/or minimize toxicity and adverse effects. Also, medications commonly used in conjunction with ipilimumab, such as other immune modulators (nivolumab) or corticosteroids, should be prepared and ready to use. Nurses and other health care workers who generally supervise the patient while receiving medical therapy should be trained and informed to look out for changes in the baseline from the patient, including examining for new rashes, observing for signs of endocrinopathies, and questioning for changes in bowel movements. The physician should be tasked with properly delegating these tasks and informing the members of his staff. This ensures that the physician is aware of the changes in the patient and can be prepared for any changes. Additionally, the physician needs to be mindful of the various common and uncommon adverse effects of ipilimumab and continuously monitor the patient for these changes. Also, there have not been many studies to determine specific indications or adverse effects of the drug, and the alert physician should be continually be looking for improvements to treatment and can consider different options in therapy, such as reduced drug dosage, increased duration between doses, or combination therapy with other medications.
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