title: CAR T-cell therapy: toxicity and the relevance of preclinical models.
abstract: Chimeric antigen receptor (CAR) T cells form part of a broad wave of immunotherapies that are showing promise in early phase cancer clinical trials. This clinical delivery has been based upon preclinical efficacy testing that confirmed the proof of principle of the therapy. However, CAR T-cell therapy does not exist alone as T cells are generally given in combination with patient preconditioning, most commonly in the form of chemotherapy, and may also include systemic cytokine support, both of which are associated with toxicity. Consequently, complete CAR T-cell therapy includes elements where the toxicity profile is well known, but also includes the CAR T cell itself, for which toxicity profiles are largely unknown. With recent reports of adverse events associated with CAR T-cell therapy, there is now concern that current preclinical models may not be fit for purpose with respect to CAR T-cell toxicity profiling. Here, we explore the preclinical models used to validate CAR T-cell function and examine their potential to predict CAR T-cell driven toxicities for the future.
authors.affiliation: Clinical & Experimental Immunotherapy Group, Institute of Cancer Sciences, Academic Healthcare Science Centre, University of Manchester, Manchester Paterson Building, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: Kalaitsidou
authors.affiliation: Clinical & Experimental Immunotherapy Group, Institute of Cancer Sciences, Academic Healthcare Science Centre, University of Manchester, Manchester Paterson Building, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Gray
authors.initials: G
authors.lastname: Kueberuwa
authors.affiliation: Clinical & Experimental Immunotherapy Group, Institute of Cancer Sciences, Academic Healthcare Science Centre, University of Manchester, Manchester Paterson Building, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: Antje
authors.initials: A
authors.lastname: Schütt
authors.affiliation: Clinical & Experimental Immunotherapy Group, Institute of Cancer Sciences, Academic Healthcare Science Centre, University of Manchester, Manchester Paterson Building, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
authors.forename: David Edward
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins
keywords: CAR T cells; adoptive cell therapy; cytokine storm; preclinical models; toxicity