Neurological updates: neurological complications of CAR-T therapy
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NEUROLOGICAL UPDATE
Neurological updates: neurological complications of CAR‑T therapy Emma C. Tallantyre1,2 · Nia A. Evans3,4 · Jack Parry‑Jones5 · Matt P. G. Morgan1,5 · Ceri H. Jones6 · Wendy Ingram6 Received: 7 September 2020 / Revised: 17 September 2020 / Accepted: 18 September 2020 © The Author(s) 2020
Abstract Chimeric antigen receptor (CAR)-expressing T cells now offer an effective treatment option for people with previously refractory B cell malignancies and are under development for a wide range of other tumours. However, neurological toxicity is a common complication of CAR-T cell therapy, seen in over 50% of recipients in some cohorts. Since 2018, the term immune effector cell-associated neurotoxicity syndrome (ICANS) has been used to describe and grade neurotoxicity seen after CAR-T cells and other similar therapies. ICANS following CAR-T therapy is usually self-limiting but can necessitate admission to the intensive care unit and is rarely fatal. As CAR-T therapies enter routine clinical practice, it is important for neurologists to be aware of the nature of neurological complications. Here, we summarise the clinical manifestations, mechanisms, investigations and recommended treatment of CAR-T-related neurotoxicity, focusing on the licensed CD19 products. Keywords Neurological · Chimeric antigen receptor T cell (CAR-T) · Adverse events · Side-effects
Introduction The development of chimeric antigen receptor (CAR)expressing T cells represents a major advance for the treatment of haematological malignancy. Autologous or allogeneic T cells are leukapheresed and genetically modified ex vivo by viral transduction to generate an advanced therapy medicinal product (ATMP; Fig. 1). The T cells are modified to express a CAR, which features an antigen detecting single-chain variable fragment, expressed on the cell surface acting as the target binding domain. This extracellular antigen recognition moiety is fused via a transmembrane domain to an intracellular co-stimulatory domain (such as * Emma C. Tallantyre [email protected] 1
School of Medicine, Cardiff University, Cardiff, UK
2
Department of Neurology, Cardiff and Vale University Health Board, Cardiff, UK
3
Department of Pharmacy, Cardiff and Vale University Health Board, Cardiff, UK
4
Midlands and Wales Advanced Therapy Treatment Centre, Birmingham, UK
5
Department of Critical Care, Cardiff and Vale University Health Board, Cardiff, UK
6
Department of Haematology, Cardiff and Vale University Health Board, Cardiff, UK
CD28 and 4-1BB) and a CD3-zeta activation domain. The transduced anti-tumour CAR-T cells are expanded ex vivo and infused into the patient, following lymphocyte depleting chemotherapy to facilitate CAR-T cell expansion in the host. The intrinsic activation mechanism within CAR-T cells allows them to become fully activated and acquire the full repertoire of effector functions on encountering tumour antigen, without the need for major histocompatibility complexepitope presentation. Autologous anti-CD19 CAR-T cel
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