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When engineered T cells or a bispecific antibody switch on, the immune system can overshoot. The first sign is a fever, and the treatment is a drug that blocks the main signal, given early. A smaller number of people become confused or drowsy, which is graded and treated separately.
Cytokine release syndrome is graded by the ASTCT consensus criteria on three things only: fever, whether vasopressors are needed, and whether oxygen is needed. Grade 1 is fever alone. Grade 2 adds low-flow oxygen or hypotension responding to fluids. Grade 3 adds a single vasopressor or high-flow oxygen. Grade 4 adds multiple vasopressors or positive-pressure ventilation. Management escalates with grade: paracetamol and fluids; tocilizumab, an IL-6 receptor antibody, for grade 2 and above or for persistent grade 1; corticosteroids added for grade 3 and 4 or when tocilizumab does not work; intensive care for grade 4. Tocilizumab is given early rather than held back, because early use does not appear to reduce CAR-T efficacy.
ICANS, immune effector cell-associated neurotoxicity syndrome, is graded on the ICE score (orientation, naming, following commands, writing, attention), level of consciousness, seizures, motor findings and raised intracranial pressure or cerebral oedema. Handwriting deteriorates before anything else in many patients, which is why a daily written sentence is part of the observation chart. Corticosteroids, usually dexamethasone, are the treatment; tocilizumab does not cross into the brain and does not help ICANS alone. Seizure prophylaxis with levetiracetam is used with the products that carry the highest risk.
The risk differs by product and disease. Grade 3 or worse cytokine release syndrome was 13 per cent in ZUMA-1 and grade 3 or higher neurological events 28 per cent; in TRANSFORM with lisocabtagene maraleucel, grade 3 cytokine release syndrome was 1 per cent and grade 3 neurological events 4 per cent. Bispecific antibodies with step-up dosing sit lower again: 1.7 per cent grade 3 or worse cytokine release syndrome in the follicular cohort of ELM-2.
Late immune effector cell toxicities are now recognised too: prolonged cytopenias, a haemophagocytic picture, and an increased risk of infection for months.
Backbone ribbon from PDB 8J6F. RCSB PDB 8J6F. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
Showing the molecule this term concerns: Tocilizumab.
Shares ZUMA-5, Odronextamab, The CAR-T pathway in lymphoma: referral, apheresis, bridging and the waiting, Mosunetuzumab.
Shares Odronextamab, Mosunetuzumab, ICANS (neurotoxicity), Epcoritamab.
Shares Brexucabtagene autoleucel, Lisocabtagene maraleucel, Mosunetuzumab, Axicabtagene ciloleucel.
Shares Mosunetuzumab, Epcoritamab, Glofitamab, Mantle cell lymphoma.
Shares Brexucabtagene autoleucel, Lisocabtagene maraleucel, Axicabtagene ciloleucel, Tisagenlecleucel.
Shares Mosunetuzumab, Epcoritamab, Glofitamab, Mantle cell lymphoma.
Shares ZUMA-1, TRANSFORM, The CAR-T pathway in lymphoma: referral, apheresis, bridging and the waiting, Lisocabtagene maraleucel.
Shares TRANSFORM, Lisocabtagene maraleucel, ICANS (neurotoxicity), Cytokine release syndrome (CRS).