IMMU-15. PHASE I TRIAL OF GD2.CART-CELLS AUGMENTED WITH A CONSTITUTIVELY ACTIVE INTERLEUKIN-7 RECEPTOR (C7R) FOR TREATMENT OF HIGH-GRADE PEDIATRIC CNS TUMORS

BACKGROUND: Treatment of pediatric CNS tumors with T-cells modified with chimeric antigen receptors (CARTs) provides an innovative approach. We employ GD2-directed CART-cells (GD2.CARTs) modified to express a constitutively active interleukin-7 receptor (C7R) to increase GD2.CART survival and function independent of external cytokines, thereby augmenting activity against GD2-expressing CNS malignancies. METHODS: In a Phase I study, we investigated the safety of intravenous GD2.CART therapy for pediatric patients with H3K27-altered diffuse midline glioma (DMG) or other GD2-expressing recurrent CNS tumors. We used a 3 + 3 design in which the first treatment cohort received GD2.CARTs without C7R, while subsequent cohorts received GD2.CARTs co-transduced with C7R (C7R-GD2.CARTs) at two dose levels. As a secondary endpoint we measured disease response 6 weeks after CART infusion. RESULTS: 12 patients were treated without dose limiting toxicity. The first cohort (n=3: thalamic DMG, spinal DMG, recurrent AT/RT) received GD2.CARTs without C7R at 1x10(7) cells/m(2). No toxicity was observed and all 3 patients had clinical neurological improvement lasting approximately 4 weeks before disease progression. The next two cohorts received C7R-GD2.CARTs at 1x10(7) cells/m(2) (n=3) and 3x10(7) cells/m(2) (n=6). Mild tumor inflammation associated neurotoxicity was observed in 7 of 9 (78%) patients, which was controlled with anakinra without need for corticosteroids. Cytokine release syndrome (CRS) was observed in 5 of 9 (56%) cases [grade 1 (n=4), grade 3 (n=1)], resolving with tocilizumab. Eight of 9 patients receiving C7R-GD2.CARTs had clinical improvement or stability for more than 8 weeks (up to 10 months at last follow-up) and received repeat cell infusions at 6 week intervals (range 2-4 cycles). Partial radiologic responses were confirmed for 2 of 7 (29%) patients with DMG. CONCLUSION: Intravenous treatment with C7R-modified GD2.CARTs was well tolerated in children with CNS tumors, and the duration of clinical improvement was extended by C7R co-expression.