Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.
Blood Adv
; 7(9): 1725-1738, 2023 05 09.
Article
em En
| MEDLINE
| ID: mdl-36453632
ABSTRACT
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared with FMC63 CAR T cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B cells present in the manufacture.
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1
Base de dados:
MEDLINE
Assunto principal:
Citocinas
/
Receptores de Antígenos Quiméricos
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article