Immunology · Year 2 · from Immunology
Case 1: Metastatic Melanoma Treated with Checkpoint Inhibitors
Patient Presentation
Demographics: 58-year-old male
Chief Complaint: Follow-up for metastatic melanoma treatment
History of Present Illness: The patient was diagnosed with BRAF wild-type metastatic melanoma 3 months ago with lung and liver metastases. He was started on combination checkpoint inhibitor therapy with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). After 4 cycles, imaging shows significant tumor regression, but he now presents with new symptoms of fatigue, diarrhea (6-8 watery stools/day), and skin rash.
Past Medical History:
- Melanoma diagnosed 3 months ago (BRAF wild-type)
- Hypertension
- No autoimmune disease history
Medications:
- Ipilimumab/nivolumab combination (4 cycles completed)
- Lisinopril 10 mg daily
Physical Examination:
- Blood pressure: 102/68 mmHg (lower than baseline)
- Heart rate: 92 bpm
- Temperature: 37.1C
- General: Fatigued appearance
- Skin: Diffuse maculopapular rash on trunk and extremities
- Abdomen: Mild diffuse tenderness, hyperactive bowel sounds
- Thyroid: Normal size
Workup and Results
Laboratory Studies:
- WBC: 8,200/mcL (normal)
- Hemoglobin: 12.8 g/dL
- TSH: 12.4 mU/L (elevated)
- Free T4: 0.6 ng/dL (low)
- Cortisol (AM): 4.2 mcg/dL (low-normal)
- CRP: 45 mg/L (elevated)
- Stool studies: Negative for infection
Imaging:
- CT chest/abdomen: 60% reduction in tumor burden compared to baseline
Colonoscopy:
- Diffuse colonic inflammation with ulceration
- Biopsy: Lymphocytic infiltration consistent with immune-mediated colitis
Clinical Image
Colonoscopy demonstrating immune-related colitis with diffuse inflammation, ulceration, and erythema. Histology shows lymphocytic infiltration of the colonic mucosa, characteristic of checkpoint inhibitor-induced colitis.
Diagnosis
Immune-Related Adverse Events (irAEs) from Checkpoint Inhibitor Therapy:
- Grade 3 immune-mediated colitis
- Checkpoint inhibitor-induced hypothyroidism
- Grade 2 cutaneous irAE (rash)
Discussion
This case illustrates checkpoint inhibitor toxicity:
- Mechanism of irAEs: The lecture explains that irAEs result from autoimmune inflammation in normal tissues. By releasing the "brakes" on T cells (blocking CTLA-4 and PD-1), checkpoint inhibitors enhance anti-tumor immunity but also permit autoreactivity.
- Combination Therapy Toxicity: The lecture notes that combining anti-CTLA-4 and anti-PD-1 increases efficacy but also toxicity. These agents work through different mechanisms: ipilimumab enhances T cell priming, while nivolumab reinvigorates exhausted T cells.
- Common irAE Sites: The lecture identifies skin, GI tract, liver, and endocrine glands as most commonly affected organs. This patient demonstrates colitis, thyroiditis, and dermatitis.
- Endocrine irAEs: Thyroiditis from checkpoint inhibitors often progresses to permanent hypothyroidism requiring lifelong replacement. Primary adrenal insufficiency and hypophysitis can also occur.
Treatment Plan
- Colitis Management (Grade 3):
- Hold checkpoint inhibitors
- High-dose corticosteroids (methylprednisolone 1-2 mg/kg/day)
- If no improvement in 3 days: add infliximab (anti-TNF)
- Supportive care: IV fluids, electrolyte replacement
- Hypothyroidism:
- Levothyroxine replacement (permanent treatment likely needed)
- Does not require holding immunotherapy
- Rash (Grade 2):
- Topical corticosteroids
- Oral antihistamines
- Monitoring:
- Daily clinical assessment
- Repeat TSH in 6 weeks
- Morning cortisol to rule out adrenal insufficiency
- Future Immunotherapy:
- May resume anti-PD-1 monotherapy after colitis resolves
- Avoid ipilimumab (higher colitis risk)
Teaching Points
- irAEs result from T cell activation against normal tissues
- Combination checkpoint inhibitors increase efficacy and toxicity
- Grade 3-4 irAEs require high-dose corticosteroids
- Endocrine irAEs (thyroiditis) may require lifelong hormone replacement
- Tocilizumab (anti-IL-6) treats CRS; corticosteroids treat most irAEs