Cytokine release syndrome and neurotoxicity afterCD19 chimeric antigen receptor‐modified (CAR‐) T cell therapy

Abstract

Chimeric antigen receptor-modified (CAR)-T cells have demonstrated impressive results in the treatment of haematological malignancies. However, cytokine release syndrome (CRS) and neurotoxicity are common toxicities which are potentially life-threatening in severe cases. Risk factors for CRS and neurotoxicity identified so far include disease burden, lymphodepletion intensity and CAR-T cell dose administered. Risk-adapted dosing, with lower CAR-T cell doses administered to B-cell acute lymphoblastic leukaemia patients with high marrow blast counts, has been successful at decreasing severe CRS rates in this population. Intervention with therapies, such as tocilizumab and corticosteroids, have been effective at ameliorating toxicity, enabling CAR-T cells to be administered safely to many patients without significantly compromising efficacy. Deeper understanding of the pathophysiology of underlying CRS and neurotoxicity will enable the development of novel approaches to reduce toxicity and improve outcomes.

Translating IL-6 biology into effective treatments

“…CAR T cells are ex vivo-modified T cells from patients with cancer that are reprogrammed to lyse tumour cells when bound to a specific cancer cell surface protein. However, ~70% of patients treated with a CD19 CAR T cell therapy develop CRS 135 . CRS leads to headache, fever, chills, severe nausea, vomiting, diarrhoea, musculoskeletal pain, dyspnoea, hypotension and tachycardia and in severe cases can be fatal.…”

Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor T Cell Therapy

“…CRS is a systemic inflammatory response that arises within several days of the CAR T infusion and may manifest as fever, hypotension, capillary leak syndrome, and multiorgan failure. Severe CRS may affect 10% to 40% of patients [17]. Acute neurotoxicity can manifest as a multitude of different neurologic adverse events, including but not limited to confusion, expressive aphasia, obtundation, myoclonus, and seizure.…”

“…Acute neurotoxicity can manifest as a multitude of different neurologic adverse events, including but not limited to confusion, expressive aphasia, obtundation, myoclonus, and seizure. Severe neurotoxicity may affect 10% to 40% of patients [17]. CAR T cell product, CAR T cell dose, and patients' characteristics (such as disease treated, disease burden, or prior neurologic conditions) may affect rates and manifestations of CRS and neurotoxicity.…”

Central nervous system emergencies in haematological malignancies

“…Cytokine release syndrome and neurotoxicity may be observed in the same patients. A strong correlation between the serum IL6 levels and severity of CRS after CAR T cell therapy was reported (Hay, ). Hence, tocilizumab or the chimeric anti‐IL6 monoclonal antibody, siltuximab, have become the drugs of choice for the management of moderate‐to severe CRS.…”