Halliwell, Emma;
Vitali, Alice;
Muller, Henrike;
Alonso-Ferrero, Maria;
Barisa, Marta;
Gavriil, Artemis;
Piapi, Alice;
... Anderson, John; + view all
(2022)
Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells.
Cytotherapy
10.1016/j.jcyt.2022.10.007.
(In press).
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Abstract
Background aims: The targeting of solid cancers with chimeric antigen receptor (CAR) T cells faces many technological hurdles, including selection of optimal target antigens. Promising pre-clinical and clinical data of CAR T-cell activity have emerged from targeting surface antigens such as GD2 and B7H3 in childhood cancer neuroblastoma. Anaplastic lymphoma kinase (ALK) is expressed in a majority of neuroblastomas at low antigen density but is largely absent from healthy tissues. / Methods: To explore an alternate target antigen for neuroblastoma CAR T-cell therapy, the authors generated and screened a single-chain variable fragment library targeting ALK extracellular domain to make a panel of new anti-ALK CAR T-cell constructs. / Results: A lead novel CAR T-cell construct was capable of specific cytotoxicity against neuroblastoma cells expressing low levels of ALK, but with only weak cytokine and proliferative T-cell responses. To explore strategies for amplifying ALK CAR T cells, the authors generated a co-CAR approach in which T cells received signal 1 from a first-generation ALK construct and signal 2 from anti-B7H3 or GD2 chimeric co-stimulatory receptors. The co-CAR approach successfully demonstrated the ability to avoid targeting single-antigen-positive targets as a strategy for mitigating on-target off-tumor toxicity. / Conclusions: These data provide further proof of concept for ALK as a neuroblastoma CAR T-cell target.
| Type: | Article |
|---|---|
| Title: | Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.jcyt.2022.10.007 |
| Publisher version: | https://doi.org/10.1016/j.jcyt.2022.10.007 |
| Language: | English |
| Additional information: | Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | ALK, anaplastic lymphoma kinase, CAR T cells, chimeric antigen receptor, neuroblastoma |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10159293 |
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