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Ipilimumab: Mechanism of Action, Adverse Effects, Contraindications, and Dosage

Mechanism of Action of Ipilimumab

Ipilimumab is a human IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4). CTLA-4 is an inhibitory immune checkpoint on T cells. By preventing CTLA-4–mediated down-regulation, ipilimumab enhances T-cell priming and antitumor activity.

Treatment of Advanced Renal Cell Carcinoma with Ipilimumab in Combination with Nivolumab

For metastatic renal cell carcinoma (mRCC), the combination of nivolumab plus ipilimumab is an established first-line option for patients with intermediate- or poor-risk disease. The CheckMate-214 study showed significant advantages in progression-free survival and overall survival (56 vs. 38 months at 5-year follow-up) compared with sunitinib in first-line therapy of patients with intermediate and poor prognosis. The combination also has a good response in patients with sarcomatoid renal cell carcinoma (Albiges et al., 2020).

Pharmacokinetics of Ipilimumab

Administer ipilimumab by intravenous infusion over 30 minutes. The mean terminal half-life is approximately 15 days; clearance occurs via catabolic protein metabolism.

Adverse Effects of Ipilimumab

Ipilimumab can cause immune-mediated adverse reactions that may occur during treatment or after discontinuation. Please also see the section adverse effects of checkpoint inhibitors. Depending on severity, clinicians should hold or permanently discontinue ipilimumab and initiate high-dose corticosteroids (e.g., methylprednisolone 1–2 mg/kg/day) followed by a taper; add additional immunosuppression if refractory. Educate patients to report symptoms promptly.

• Gastrointestinal: Immune-mediated colitis and diarrhea; risk of bowel perforation if untreated.
• Hepatic: Immune-mediated hepatitis with transaminase/bilirubin elevation.
• Endocrine: Hypophysitis (pituitary inflammation), hypothyroidism or hyperthyroidism, adrenal insufficiency, type 1 diabetes (including diabetic ketoacidosis).
• Pulmonary: Pneumonitis (less frequent than with PD-1/PD-L1 inhibitors but reported).
• Dermatologic: Rash, pruritus; severe cutaneous adverse reactions are rare.
• Other: Nephritis, uveitis, neurologic syndromes, hematologic cytopenias; infusion reactions.

Contraindications to Ipilimumab

There are no absolute contraindications. In practice, do not initiate therapy in pregnancy or during breastfeeding, and permanently discontinue for grade 4 immune-mediated toxicity or life-threatening events. Avoid re-challenge after severe, steroid-refractory immune-related adverse events.

Drug Interactions with Ipilimumab

Concurrent systemic corticosteroids or other immunosuppressants may diminish the antitumor efficacy of ipilimumab and should be avoided unless required to manage immune-mediated toxicity. Live vaccines are generally not recommended during treatment.

There is a complex interplay between the gut microbiome and checkpoint inhibitor activity. Prior or early exposure to systemic antibiotics has been associated with reduced efficacy in observational studies.

Dosing of Ipilimumab in Combination with Nivolumab for Treatment of mRCC

• Induction: nivolumab 3 mg/kg IV plus ipilimumab 1 mg/kg IV every 3 weeks for 4 doses.
• Maintenance: continue nivolumab monotherapy per labeling (e.g., 240 mg every 2 weeks or 480 mg every 4 weeks) until disease progression or unacceptable toxicity.

Monitoring During Therapy with Ipilimumab

Before each treatment cycle of ipilimumab, assess for symptoms and laboratory abnormalities. Provide thorough patient education and perform targeted review of systems across all organ systems to ensure prompt diagnostics, treatment pause or discontinuation, and timely steroid initiation when indicated.

• Thorough medical history and physical examination: Inspect skin and oral mucosa; auscultate lungs; perform a focused neurologic examination; measure the blood pressure.
• Laboratory monitoring: Complete blood count with differential; electrolytes; liver function tests and bilirubin; lipase; creatine kinase and troponin; coagulation studies; blood glucose; creatinine; TSH and free T4; LDH; CRP.

References

L. Albiges, N. M. Tannir, M. Burotto, D. McDermott, E. R. Plimack, and R. J. Motzer, “Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial.,” ESMO open, vol. 5, no. 6, p. e001079, 2020.

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