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- W2956121311 abstract "Abstract Background: Anti-disialoganglioside (GD2) specific CAR T-cell therapy has shown limited efficacy in children with recurrent/refractory neuroblastoma (NBL). A recent pre-clinical study demonstrated significant neurotoxicity in mice treated with CAR T-cells bearing a high-affinity anti-GD2 short chain variable fragments (scFv; Richman S et al. 2017). To devise a safe and more efficacious CAR T-cells, we developed a gated CAR T-cell system utilizing the Syn-Notch technology. Methods: GD2 and CD19 specific Syn-Notch gated systems were constructed by linking corresponding scFv to the Notch core followed by Gal4Vp64. Upon target recognition, Gal4VP64-dependent UAS element would initiate expression of the B7H3-BBZ CAR. Reporter activity of CD19 or GD2 Syn-Notch systems were monitored using flow cytometry after exposure to CD19+ transduced CHLA255 NBL cell line. In vitro cytotoxicity was assessed using DIMSCAN and xCELLigence impedance assays at varying Effector: Target ratios. NSG mice with established metastatic CHLA255(GD2+CD19+) NBL were treated with 1x10^7 transduced and control T cells and monitored for disease burden. Results and discussion: Jurkat and human primary T cells were successfully transduced with the Syn-Notch system. GD2-Notch-Gal4VP64 and CD19-Notch-Gal4VP64 T-cells effectively activated downstream reporter in exposure to CHLA255(GD2+CD19+) within 6 hours of exposure but not in the presence of NBL cells lacking GD2 or CD19. The GD2 system exhibited greater leakiness than the CD19 counterpart. GD2- Syn-Notch-B7H3-BBZ or CD19- Syn-Notch-B7H3-BBZ CAR T-cells demonstrated statistically significant cytotoxicity against CHLA255(GD2+CD19+) NBL cell line. Preliminary in vivo data also show the anti-tumor effect of these gated CAR systems compared to mock-transduced T-cells. Conclusions: We have successfully established a novel GD2-B7H3 gated system using the Syn-Notch technology, and demonstrate successful specificity to both antigen targets. This system increases the specificity of CAR T-cells against GD2 and B7H3 positive neuroblastoma tumors and likely minimize GD2-induced toxicity. These gated CARs show great promise for establishing immunotherapies that maximize tumor specificity while minimizing toxicity. Citation Format: Babak Moghimi, Sakunthala Muthugounder, Shahab Asgharzadeh. Improving efficacy and accuracy of CAR-T cells for neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1437." @default.
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- W2956121311 date "2019-07-01" @default.
- W2956121311 modified "2023-09-27" @default.
- W2956121311 title "Abstract 1437: Improving efficacy and accuracy of CAR-T cells for neuroblastoma" @default.
- W2956121311 doi "https://doi.org/10.1158/1538-7445.am2019-1437" @default.
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