Self-regulating CAR-T cells modulate cytokine release syndrome in adoptive T-cell therapy.
J Exp Med
; 221(6)2024 Jun 03.
Article
em En
| MEDLINE
| ID: mdl-38607370
ABSTRACT
Cytokine release syndrome (CRS) is a frequently observed side effect of chimeric antigen receptor (CAR)-T cell therapy. Here, we report self-regulating T cells that reduce CRS severity by secreting inhibitors of cytokines associated with CRS. With a humanized NSG-SGM3 mouse model, we show reduced CRS-related toxicity in mice treated with CAR-T cells secreting tocilizumab-derived single-chain variable fragment (Toci), yielding a safety profile superior to that of single-dose systemic tocilizumab administration. Unexpectedly, Toci-secreting CD19 CAR-T cells exhibit superior in vivo antitumor efficacy compared with conventional CD19 CAR-T cells. scRNA-seq analysis of immune cells recovered from tumor-bearing humanized mice revealed treatment with Toci-secreting CD19 CAR-T cells enriches for cytotoxic T cells while retaining memory T-cell phenotype, suggesting Toci secretion not only reduces toxicity but also significantly alters the overall T-cell composition. This approach of engineering T cells to self-regulate inflammatory cytokine production is a clinically compatible strategy with the potential to simultaneously enhance safety and efficacy of CAR-T cell therapy for cancer.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Citocinas
/
Síndrome da Liberação de Citocina
Limite:
Animals
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos