Targeting of low ALK antigen density neuroblastoma using AND logic-gate engineered CAR-T cells.
Cytotherapy
; 25(1): 46-58, 2023 01.
Article
em En
| MEDLINE
| ID: mdl-36396552
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.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Receptores de Antígenos de Linfócitos T
/
Neuroblastoma
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article