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.
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April 2016
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Cover Image
Endoplasmic reticulumendosome contact sites. This pseudo-colored electron microscopy image shows the formation of inter-organelle membrane contact sites between late endosomes (magenta) and the endoplasmic reticulum (ER; green). This tethering results from the interaction between two ER-anchored proteins (VAP-A and VAP-B) and the late endosomeanchored protein STARD3NL. Mitochondria: brown; nucleus: blue. For further details see pp. 493-498. Image kindly provided by Fabien Alpy. - PDF Icon PDF LinkTable of Contents
Review Article|
April 11 2016
Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?
Vanesa Alonso-Camino;
Vanesa Alonso-Camino
*Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Madrid, Spain
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Seandean Lykke Harwood;
Seandean Lykke Harwood
†Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000 C Aarhus, Denmark
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Ana Álvarez-Méndez;
Ana Álvarez-Méndez
‡FEBIO Research Group, Universidad Complutense de Madrid, 28040 Madrid, Spain
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Luis Alvarez-Vallina
Luis Alvarez-Vallina
1
†Immunotherapy and Cell Engineering Laboratory, Department of Engineering, Aarhus University, 8000 C Aarhus, Denmark
1To whom correspondence should be addressed (email lav@eng.au.dk).
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Publisher: Portland Press Ltd
Received:
February 18 2016
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2016 Authors; published by Portland Press Limited
2016
Biochem Soc Trans (2016) 44 (2): 406–411.
Article history
Received:
February 18 2016
Citation
Vanesa Alonso-Camino, Seandean Lykke Harwood, Ana Álvarez-Méndez, Luis Alvarez-Vallina; Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?. Biochem Soc Trans 15 April 2016; 44 (2): 406–411. doi: https://doi.org/10.1042/BST20150286
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