title: Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?
abstract: Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery.
authors.affiliation: Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Alonso-Camino
authors.affiliation: Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000 C Aarhus, Denmark.
authors.forename: Seandean Lykke
authors.initials: SL
authors.lastname: Harwood
authors.affiliation: FEBIO Research Group, Universidad Complutense de Madrid, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Álvarez-Méndez
authors.affiliation: Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000 C Aarhus, Denmark lav@eng.au.dk.
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Vallina
mesh_terms: D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: CAR-T-cells; CARbodies; chimaeric antigen receptor; solid tumours; toxicity