What is Ipilimumab?
Ipilimumab is a humanized monoclonal antibody that targets CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), a key immune checkpoint receptor that downregulates immune activation. By blocking CTLA-4, ipilimumab enhances T-cell activation and proliferation, promoting an immune response against cancer cells.
It is primarily used in combination with nivolumab (anti-PD-1 antibody) for treating various advanced or metastatic cancers, including melanoma and several other solid tumors.
Indications of Ipilimumab (2025 Update)
Ipilimumab is approved for use alone or in combination with nivolumab for treatment of the following conditions:
- Advanced or metastatic melanoma:
- As adjuvant therapy after surgical resection of melanoma with lymph node involvement
- For unresectable or metastatic disease
- Colorectal cancer:
- For adults and children 12 years and older with metastatic microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer that has progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment.
- Administered with nivolumab.
- Hepatocellular carcinoma (HCC):
- Used in combination with nivolumab in patients previously treated with sorafenib or other systemic therapies.
- Malignant pleural mesothelioma:
- First-line treatment in unresectable cases, combined with nivolumab.
- Other solid tumors (off-label or in clinical trials):
- Including renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), and others, usually in combination with nivolumab or other agents.
Mechanism of Action
Ipilimumab is an antibody that blocks CTLA-4, a receptor expressed on activated T cells that normally acts as an immune “brake” by downregulating immune responses. By inhibiting CTLA-4, ipilimumab:
- Prevents T-cell inactivation
- Enhances T-cell activation and proliferation
- Facilitates the expansion of tumor-specific cytotoxic T lymphocytes
- Promotes anti-tumor immunity
This immune activation can also lead to immune-related side effects due to loss of self-tolerance.
Ipilimumab Dosage and Administration
For Metastatic Melanoma:
- Adults and children ≥12 years:
- 3 mg/kg IV infusion over 90 minutes every 3 weeks for a total of 4 doses.
- Adjuvant therapy for melanoma (post-surgery with lymph node involvement):
- 10 mg/kg IV over 90 minutes every 3 weeks for 4 doses, followed by maintenance doses of 10 mg/kg every 12 weeks for up to 3 years or until disease recurrence or unacceptable toxicity.
Combination with Nivolumab:
- Various dosing schedules exist depending on cancer type (e.g., 1 mg/kg ipilimumab + 3 mg/kg nivolumab every 3 weeks for 4 doses, then nivolumab maintenance).
Important Administration Notes:
- Administer intravenously as a 90-minute infusion.
- Flush IV line with 0.9% sodium chloride or 5% dextrose after infusion.
- Do not mix or infuse simultaneously with other drugs through the same IV line.
Common and Serious Side Effects
Ipilimumab can cause a broad range of immune-related adverse events (irAEs), which require close monitoring:
Frequent Side Effects:
- Fatigue, rash, diarrhea, pruritus (itching)
- Endocrine dysfunction: hypothyroidism, hyperthyroidism, hypophysitis
- Hepatitis (elevated liver enzymes)
- Colitis with diarrhea, potentially severe and life-threatening
- Pneumonitis (lung inflammation)
- Nephritis (kidney inflammation)
- Neurologic effects: neuropathy, meningitis-like symptoms
Symptoms that require immediate medical attention:
- Severe or bloody diarrhea, abdominal pain
- Shortness of breath, chest pain, cough
- Severe headache, vision changes, confusion, seizures
- Severe rash with blistering or peeling skin
- Yellowing of skin or eyes, dark urine
- Joint pain or swelling, muscle weakness
Other reported effects:
- Sleep disturbances
- Decreased urine output or swelling in legs/feet
- Weight loss, increased thirst or urination (signs of diabetes or adrenal insufficiency)
- Memory or mood changes
Drug Interactions
Ipilimumab’s immune-modulating effects mean that:
- Immunosuppressants (like corticosteroids) may reduce efficacy, but are necessary to manage irAEs.
- There are no major direct metabolic drug interactions via cytochrome P450 enzymes.
Some medications may affect the immune system or absorption of other agents but do not specifically interact with ipilimumab. Examples include:
- Antacids and proton pump inhibitors (e.g., omeprazole, pantoprazole) — no direct interaction, but always verify with healthcare provider.
- NSAIDs (e.g., ibuprofen) and H2 blockers (famotidine) — caution advised.
Precautions and Safety Information
- Inform your doctor about all medications, supplements, and vaccinations before starting ipilimumab.
- Avoid live vaccines during and after treatment until cleared by your oncologist.
- Monitor for symptoms of irAEs regularly; early detection and treatment are critical.
- Regular blood tests (liver, kidney, thyroid function) recommended.
- Use cautiously in patients with pre-existing autoimmune diseases or organ transplants.
- Pregnancy and breastfeeding are contraindicated during treatment due to potential fetal harm.
Storage
- Store the diluted solution at 2°C to 8°C (36°F to 46°F) or room temperature (20°C to 25°C, 68°F to 77°F) for up to 24 hours before use.
- Do not freeze or shake.
Contraindications
- Known hypersensitivity to ipilimumab or any component of the formulation.
- Active autoimmune disease requiring systemic treatment.
- Uncontrolled infections.
- Pregnancy or lactation — potential risk to fetus or infant.
- Severe endocrine disorders such as untreated thyroid disease or adrenal insufficiency.
- Severe peripheral neuropathy or other severe neurological disorders.
Summary
Ipilimumab is a CTLA-4 immune checkpoint inhibitor that enhances the immune system’s ability to attack cancer cells, primarily used in combination with nivolumab for advanced melanoma and several other malignancies. Its unique mechanism offers substantial clinical benefit but requires vigilant monitoring for immune-related toxicities. Dosage regimens vary by indication and patient age, with treatment typically given as intravenous infusions over several weeks.