CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma.
Nat Commun
; 15(1): 7141, 2024 Aug 21.
Article
em En
| MEDLINE
| ID: mdl-39164224
ABSTRACT
Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Matadoras Naturais
/
Linfócitos T
/
Imunoterapia Adotiva
/
Receptores de Antígenos Quiméricos
/
Gangliosídeos
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Imunidade Inata
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Neuroblastoma
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
/
Nature communications
Ano de publicação:
2024
Tipo de documento:
Article