Immunotherapy & Targeted Therapy Toxicities
Recognize the immune backlash, grade it, and treat it right
Checkpoint inhibitors and immune-related adverse events
Mechanism. Anti-PD-1 antibodies (nivolumab, pembrolizumab), anti-PD-L1 antibodies (atezolizumab, durvalumab), and the anti-CTLA-4 antibody ipilimumab remove inhibitory signals from T cells so they attack tumor. The same loss of tolerance produces immune-related adverse events (irAEs) that can affect any organ. Combined ipilimumab and nivolumab causes far more grade 3–4 events than any single agent.
Timing. Most irAEs appear within the first few months: rash and pruritus first, then colitis and hepatitis, then endocrinopathies. Any irAE can nevertheless appear at any time, including months after the drug has been stopped, so new symptoms in a current or former recipient are presumed immune-related until proven otherwise.
- Grade 1Usually continue the inhibitor with close monitoring.
- Grade 2Hold the inhibitor and consider prednisone 0.5–1 mg/kg/day; resume once the toxicity is grade 1 or less.
- Grade 3Hold (often permanently) and give IV methylprednisolone 1–2 mg/kg/day.
- Grade 4Discontinue permanently and give high-dose IV steroids.
- After controlTaper steroids over at least 4–6 weeks; if there is no improvement in 48–72 hours, add a second immunosuppressant. Prolonged high-dose steroids warrant Pneumocystis prophylaxis such as TMP-SMX.
Endocrinopathies are the exception to this algorithm: they are treated with hormone replacement, and the checkpoint inhibitor can usually continue.
Organ-specific irAEs
| irAE | Clues | Exclude first | Treatment beyond steroids |
|---|---|---|---|
| Dermatitis | Earliest and most common: maculopapular rash, pruritus; vitiligo in melanoma | Other drug eruptions | Topical steroids for mild disease |
| Colitis | Diarrhea, cramping, bleeding; most frequent with anti-CTLA-4 | C. difficile and other stool pathogens | Infliximab or vedolizumab if refractory |
| Hepatitis | Silent AST/ALT rise on routine labs | Viral hepatitis, alcohol, other drugs, metastases | Mycophenolate if refractory; no infliximab |
| Pneumonitis | Cough, dyspnea, hypoxia; ground-glass or organizing-pneumonia pattern | Infection (bronchoscopy if needed) | Empiric antibiotics for grade 3–4 |
| Myocarditis | Chest pain, arrhythmia, heart block; high troponin | Acute coronary syndrome | Permanent discontinuation, pulse IV steroids |
Colitis. Stool testing for C. difficile and other pathogens comes before immunosuppression, and endoscopy with biopsy confirms inflammation. Colitis that does not respond to steroids within about 3 days is treated with infliximab or vedolizumab. Antidiarrheals can mask worsening and risk toxic megacolon, and perforation is the feared complication.
Hepatitis. It is usually found as an asymptomatic transaminase rise. After other causes are excluded, steroids are given by grade; refractory cases receive mycophenolate, because infliximab is itself hepatotoxic.
Pneumonitis. It is more common with PD-1/PD-L1 blockade and in lung cancer. The inhibitor is held and steroids started for grade 2 or higher; grade 3–4 disease requires permanent discontinuation, IV methylprednisolone, and empiric antibiotics while infection is excluded.
Myocarditis. Uncommon but the most lethal irAE, it usually strikes within the first 3 months with elevated troponin and ECG changes. It overlaps with myositis (high CK, proximal weakness) and a myasthenia-like syndrome (ptosis, respiratory failure), so CK and respiratory function are checked too. The inhibitor is stopped permanently and high-dose IV methylprednisolone is started immediately.
Endocrine irAEs
| Disorder | Typical agent | Laboratory pattern | Treatment |
|---|---|---|---|
| Thyroiditis | PD-1/PD-L1 | Low TSH, high free T4, low radioiodine uptake → later high TSH | β-blocker, then levothyroxine |
| Hypophysitis | Ipilimumab | Low ACTH and cortisol, low TSH with low free T4, low gonadotropins | Hydrocortisone first, then levothyroxine |
| Primary adrenalitis | Any | High ACTH, low cortisol and aldosterone, hyponatremia, hyperkalemia | Hydrocortisone plus fludrocortisone |
| Insulin-deficient diabetes | PD-1/PD-L1 | Abrupt hyperglycemia or DKA, low C-peptide, ± GAD antibodies | Lifelong insulin |
Thyroiditis. The most common endocrine irAE begins as painless destructive thyrotoxicosis that releases preformed hormone, so methimazole and radioiodine are useless; a β-blocker controls symptoms. Permanent hypothyroidism often follows and is treated with levothyroxine. TSH and free T4 are checked regularly during therapy.
Hypophysitis. Classically caused by ipilimumab, it presents with headache and fatigue and shows pituitary enlargement on MRI. Because aldosterone secretion is preserved in central adrenal insufficiency, potassium is usually normal.
Always start hydrocortisone before levothyroxine in hypophysitis; replacing thyroid hormone first accelerates cortisol clearance and can precipitate adrenal crisis.
Checkpoint diabetes. Abrupt destruction of β cells often presents as DKA. Steroids do not reverse it, and insulin is lifelong.
CAR-T cell toxicities
| Feature | CRS | ICANS |
|---|---|---|
| Mechanism | IL-6–driven systemic inflammation after T-cell activation | Neurotoxicity from immune effector cells and cytokines |
| Features | Fever first, then hypotension and hypoxia | Confusion, expressive aphasia, impaired handwriting, tremor, seizures, cerebral edema |
| Timing | Usually within days of infusion | Accompanies or follows CRS |
| Treatment | Supportive care; tocilizumab for grade ≥2; dexamethasone if refractory or severe | Dexamethasone plus levetiracetam; tocilizumab does not help isolated ICANS |
Why tocilizumab fails in ICANS. Tocilizumab blocks the IL-6 receptor but does not cross the blood–brain barrier, so isolated neurotoxicity needs corticosteroids. CAR-T therapy also causes B-cell aplasia with hypogammaglobulinemia (treated with IVIG), prolonged cytopenias, and infections.
Targeted therapy toxicities
Trastuzumab. HER2 blockade impairs cardiomyocyte repair signaling and lowers LVEF without killing myocytes, so the injury is not dose-dependent and usually reverses, unlike anthracycline cardiomyopathy. An echocardiogram is obtained at baseline and every 3 months. A significant LVEF decline prompts holding the drug, treating heart failure if present, and rechecking in about 4 weeks, with resumption if function recovers. Prior anthracycline exposure increases risk.
EGFR antibodies. Cetuximab and panitumumab, used in RAS wild-type colorectal cancer, cause an acneiform papulopustular rash whose severity tracks with response and is treated with oral doxycycline or minocycline and topical steroids. Renal magnesium wasting requires monitoring and replacement. Severe first-dose cetuximab reactions occur in people with preexisting IgE to alpha-gal (galactose-α-1,3-galactose), often sensitized by tick bites.
Bevacizumab. Blocking VEGF-A causes hypertension, proteinuria, bleeding, GI perforation, arterial thrombosis, and poor wound healing, so the drug is stopped at least 28 days before elective surgery and resumed no sooner than 28 days after, once the wound has healed, and it is avoided in squamous lung cancer because of fatal hemoptysis.
PARP inhibitors. Olaparib, niraparib, rucaparib, and talazoparib exploit synthetic lethality in BRCA-mutated ovarian, breast, prostate, and pancreatic cancers. They cause anemia and other cytopenias, nausea, and fatigue, and carry a small risk of therapy-related MDS/AML, so CBCs are checked monthly and persistent cytopenias prompt a marrow evaluation.
ATRA and arsenic trioxide. In APL, rapid maturation of leukemic promyelocytes can trigger differentiation syndrome: fever, dyspnea, pulmonary infiltrates, pleural or pericardial effusions, weight gain, edema, hypotension, and AKI. Dexamethasone 10 mg IV twice daily is started at the first suspicion, and the drugs are interrupted temporarily if the syndrome is severe; diuretics are only supportive. Arsenic also prolongs the QT interval and can cause torsades, so potassium and magnesium are kept replete and other QT-prolonging drugs are avoided.