Thématique :
- Cancers autres (hors CCR et CHC)
Originalité :
Très original
Solidité :
A confirmer
Doit faire évoluer notre pratique :
Pas encore
Nom du veilleur :
Professeur Sylvain MANFREDI
Coup de coeur :
Journal of the National Cancer Institute (JNCI)
  2019 Apr;111(4):409-418.  
  doi: 10.1093/jnci/djy134.  
  Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer  
  Jiang H, Shi Z, Wang P, Wang C, Yang L, Du G, Zhang H, Shi B, Jia J, Li Q, Wang H, Li Z  



Claudin18.2 (CLDN18.2), a gastric-specific membrane protein, has been regarded as a potential therapeutic target for gastric cancer and other cancer types. The aim of our study was to elucidate whether chimeric antigen receptor T (CAR T) cells redirected to CLDN18.2 have the potential to be used in the treatment of this deadly disease.


CLDN18.2-specific humanized antibodies were developed using hybridoma and humanization technology. CLDN18.2-specific CAR T cells were prepared by lentiviral vector transduction. In vitro antitumor activities and cytokine production of the CAR T cells to gastric cancer cell lines were examined by cytotoxicity and ELISA assay. In vivo antitumor activities of CAR T cells were evaluated in mice bearing gastric cancer cell line and patient-derived tumor xenograft (PDX) models (n ≥ 6 mice per group). All statistical tests were two-sided.


Humanized CLDN18.2-specific hu8E5 and hu8E5-2I single-chain fragment variables (scFv) were successfully developed. CLDN18.2-specific CAR T cells were developed using hu8E5 or hu8E5-2I scFv as targeting moieties. Both hu8E5-28Z and hu8E5-2I-28Z CAR T cells comprising the CD28 costimulatory domain potently suppressed tumor growth in a cancer cell line xenograft mouse model (mean [SD] tumor volume: hu8E5-28Z = 118.0 [108.6] mm3 and hu8E5-2I-28Z group = 75.5 [118.7] mm3 vs untransduced T cell group = 731.8 [206.3] mm3 at day 29 after tumor inoculation, P < .001). Partial or complete tumor elimination was observed in CLDN18.2-positive gastric cancer PDX models treated with the hu8E5-2I-28Z CAR T cells (P < .001), which persist well in vivo and infiltrate efficiently into the tumor tissues. Although the CLDN18.2 CAR T cells could lyse target cells expressing murine CLDN18.2 (mCLDN18.2), no obvious deleterious effect on the normal organs including the gastric tissues was observed in the mice.


CLDN18.2-specific CAR T cells could be a promising treatment strategy for gastric cancer and potentially other CLDN18.2-positive tumors.


Question posée
Activité in vivo sur modèles murins de CAR T cell dirigés contre Claudin.
Question posée
Réponses impressionnantes voir complètes sur ces modèles murins.

De futures perspectives enthousiasmantes.