Abstract A025: Eradication of neuroblastoma by T-cells redirected with an optimized GD2-specific chimeric antigen receptor and IL-15

Abstract

The treatment with CD19-specific chimeric antigen receptor T-cells (CAR-Ts) has shown remarkable antitumor activity in patients with B-cell malignancies. However, the clinical benefits of CAR-Ts in solid tumors remain unclear. A compelling concern is that in patients with solid tumors CAR-Ts do not immediately encounter their cognate antigen in the circulation and thus lack the appropriate costimulatory signals necessary for full activation. We here sought to explore if expressing IL-15 in CAR-Ts would provide them with sufficient sustained survival until they engage the cognate antigen. Using the GD2-specific CAR and neuroblastoma (NB) as a tumor model, we explored the benefits of incorporating the IL-15 cytokine (and the iCaspase9 suicide gene for safety) within the CAR molecule. CAR-Ts from 12 healthy donors were transduced with an optimized GD2.CAR (encoding the CD28 endodomain) without (GD2-Ts) or with the IL15 (GD2.15.iC9-Ts) and expanded ex vivo with IL-7/IL-15 for 14 days. CAR transduction (82% ± 8% and 82% ± 12%, respectively) and ex vivo antitumor activity in 4 days co-culture at different E:T ratios were comparable. However, upon repetitive stimulation with GD2+ NB tumors (CHLA-255 and LAN-1), only GD2.15.iC9-Ts showed significantly superior expansion and antitumor activity (p Citation Format: Yuhui Chen, Chuang Sun, Leonid Metelitsa, Gianpietro Dotti, Barbara Savoldo. Eradication of neuroblastoma by T-cells redirected with an optimized GD2-specific chimeric antigen receptor and IL-15 [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A025.