malignancies that are not responsive to standard therapies. 6
CAR T-cell therapies have shown promising results in other indications and have also been studied in early stages for solid tumours. 2, 3, 5 Currently, the main pharmaceutical players leading this field are Kite Pharma( KTE-C19), Novartis( CTL019) and Pfizer( UCART19). Tisagenlecleucel( Kymriah, Novartis Pharmaceuticals Corp) and axicabtagene ciloleucel( Yescarta, Kite Pharma) have been FDA approved.
However, following CAR T-cell infusion, potentially severe and unique side effects including immune-mediated adverse events have been observed. These can be acute, delayed, mild, severe, and / or persist for the duration of the genetically modified T-cell lifespan.
CAR T-cell-related toxicities CAR T-cell therapy is associated with serious toxicities. The most acute, feared, troublesome and common toxicity in patients treated with CD19-specific CAR T-cells is cytokine release syndrome( CRS). 3, 4, 7
Other toxicities include macrophage activation syndrome / haemophagocytic lymphohistiocytosis, neurotoxicity, febrile neutropenia, tumour lysis syndrome, fever and hypogammaglobulinaemia. 3, 4, 7
CRS CRS, a potentially life-threatening condition, is a systematic inflammatory response caused by cytokines released by the infused CAR T-cells or other immune cells, such as macrophages, that might produce cytokines in response to cytokines produced by the infused CAR T-cells. 3, 6, 7 The expected time of onset varies depending on the type of CAR T-cells used. 3, 6
When CRS occurs, there is a rapid and huge release of cytokines into the patient’ s bloodstream, leading to high fevers and drops in blood pressure. 3, 6 Symptoms in general can range from mild to life-threatening. CRS caused by CAR T-cells often manifests as high fever, myalgia, fatigue, anorexia, hypotension, pulmonary oedema, and coagulopathy. 8, 9 Progressively worsening CRS can lead to multi-organ dysfunction including( but not limited to) cardiovascular, pulmonary and renal failure. Fortunately, with timely and appropriate management, CRS is reversible in the vast majority of patients despite severe abnormalities.
A modification of the Common Terminology Criteria for Adverse Events 10 has resulted in a grading mechanism suitable for grading CRS
6, 10, 11
due to T-cell therapies.
• Grade 1 symptoms: require symptomatic management
• Grade 2 symptoms: respond to moderate intervention, including oxygen requirement < 40 %, grade 2 organ toxicity, or hypotension responding to intravenous fluids or low doses of one vasopressor
• Grade 3 CRS: includes oxygen requirement ≥ 40 %, hypotension requiring high-dose or multiple vasopressors, grade 4 transaminitis, and grade 3 organ toxicity at other sites.
• Grade 4 CRS: life-threatening symptoms requiring ventilator support or grade 4 organ toxicity other than transaminitis
Management mAbs against IL-6 receptors, such as tocilizumab( approved for treatment of severe, active and progressive rheumatoid arthritis), have been used off-label for toxicity following CAR T-cell therapy. Tocilizumab has recently been FDA approved for the treatment of CAR T-cell-induced CRS. Such
Following CAR T-cell infusion, unique and potentially severe side-effects can occur
104 HHE 2018 | hospitalhealthcare. com