Chimeric antigen receptor (CAR)-T cell therapy has been clinically validated as a curative treatment for the difficult to treat malignancies of relapsed/refractory B-cell acute lymphoblastic leukaemia and lymphoma. Here, the CAR-T cells are re-directed towards a single antigen, CD19, which is recognised as a virtually ideal CAR target antigen because it has strong, uniform expression on cancer cells, and is otherwise expressed only on healthy B cells, which are ‘dispensable’. Notwithstanding the clinical success of CD19-CAR-T cell therapy, its single specificity has driven therapeutic resistance in 30% or more of cases with CD19-negative leukaemic relapses. Immune checkpoint blockade is also a highly successful cancer immunotherapeutic approach, but it will be less useful for many patients whose malignancies either lack a substantial somatic mutation load or whose tumours are intrinsically resistant. Although CAR-T cell therapy could serve this unmet medical need, it is beset by several major limitations. There is a lack of candidate antigens that would satisfy the requirements for ideal CAR targets. Biological properties such as clonal heterogeneity and micro-environmental conditions hostile to T cells are inherent to many solid tumours. Past clinical studies indicate that on-target, off-tumour toxicities of CAR-T cell therapy may severely hamper its application. Therefore, re-designing CARs to increase the number of antigen specificities recognised by CAR-T cells will broaden tumour antigen coverage, potentially overcoming tumour heterogeneity and limiting tumour antigen escape. Tuning the balance of signalling within bi-specific CAR-T cells may enable tumour targeting while sparing normal tissues, and thus minimise on-target, off-tumour toxicities.
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April 2018
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A 3D rendering of a Ubiquitin protein molecule. In this issue of Biochemical Society Transactions, Ovaa and Vertegaal discuss the role of ubiquitination and SUMO proteins in conjugation and deconjugation machineries; for details, see pages 423–436.
Review Article|
March 14 2018
Logic-gated approaches to extend the utility of chimeric antigen receptor T-cell technology
Lisa M. Ebert;
Lisa M. Ebert
1Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia
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Wenbo Yu;
Wenbo Yu
1Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia
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Tessa Gargett;
Tessa Gargett
1Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia
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Michael P. Brown
1Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia
2Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia
3School of Medicine, University of Adelaide, Adelaide, Australia
Correspondence: Michael P. Brown (michaelp.brown@sa.gov.au)
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Publisher: Portland Press Ltd
Received:
November 15 2017
Revision Received:
January 04 2018
Accepted:
January 08 2018
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Biochem Soc Trans (2018) 46 (2): 391–401.
Article history
Received:
November 15 2017
Revision Received:
January 04 2018
Accepted:
January 08 2018
Citation
Lisa M. Ebert, Wenbo Yu, Tessa Gargett, Michael P. Brown; Logic-gated approaches to extend the utility of chimeric antigen receptor T-cell technology. Biochem Soc Trans 17 April 2018; 46 (2): 391–401. doi: https://doi.org/10.1042/BST20170178
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