{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:52:57Z","timestamp":1789498377146,"version":"build-2803163510"},"reference-count":67,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4,17]]},"abstract":"<jats:p>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 \u2018dispensable\u2019. 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.<\/jats:p>","DOI":"10.1042\/bst20170178","type":"journal-article","created":{"date-parts":[[2018,3,14]],"date-time":"2018-03-14T11:20:24Z","timestamp":1521026424000},"page":"391-401","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Logic-gated approaches to extend the utility of chimeric antigen receptor T-cell technology"],"prefix":"10.1042","volume":"46","author":[{"given":"Lisa M.","family":"Ebert","sequence":"first","affiliation":[{"name":"Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Yu","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tessa","family":"Gargett","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Brown","sequence":"additional","affiliation":[{"name":"Translational Oncology Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Frome Road, Adelaide, SA 5000, Australia"},{"name":"Cancer Clinical Trials Unit, Royal Adelaide Hospital, Adelaide, Australia"},{"name":"School of Medicine, University of Adelaide, Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2018,3,14]]},"reference":[{"key":"2021111818054529300_BST-2017-0178CC1","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/nature22395","article-title":"Therapeutic T cell engineering","volume":"545","author":"Sadelain","year":"2017","journal-title":"Nature"},{"key":"2021111818054529300_BST-2017-0178CC2","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/S0022-1759(00)00343-4","article-title":"Functional expression of chimeric receptor genes in human T cells","volume":"248","author":"Eshhar","year":"2001","journal-title":"J. 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