| Title: |
Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells |
| Authors: |
Halliwell, Emma; Vitali, Alice; Muller, Henrike; Alonso-Ferrero, Maria; Barisa, Marta; Gavriil, Artemis; Piapi, Alice; Leboreiro-Babe, Clara; Gileadi, Talia; Yeung, Jenny; Pataillot-Meakin, Thomas; Fisher, Jonathan; Tucker, Lizzie; Donovan, Laura; Chesler, Lou; Chester, Kerry; Anderson, John |
| Source: |
Cytotherapy (2022) (In press). |
| Publisher Information: |
Informa Healthcare |
| Publication Year: |
2022 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
ALK; anaplastic lymphoma kinase; CAR T cells; chimeric antigen receptor; neuroblastoma |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10159293/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10159293/1/1-s2.0-S1465324922008313-main.pdf; https://discovery.ucl.ac.uk/id/eprint/10159293/ |
| Rights: |
open |
| Accession Number: |
edsbas.6B269A69 |
| Database: |
BASE |