DIPG-47. SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS
Authors: Monje Michelle , Mahdi Jasia , Majzner Robbie G , Yeom Kristen , Schultz Liora M , Richards Rebecca , Barsan Valentin , Song Kun-Wei , Kamens Jennifer , Baggott Christina , Kunicki Michael , Lim Alexandria Sung , Reschke Agnes , Mavroukakis Sharon , Egeler Emily , Moon Jennifer , Patel Shabnum , Chinnasamy Harshini , Erickson Courtney , Jacobs Ashley , Duh Allison K , Rietberg Skyler P , Tunuguntla Ramya , Klysz Dorota Danuta , Fowler Carley , Green Sean , Beebe Barbara , Carr Casey , Fujimoto Michelle , Brown Annie Kathleen , Peterson Ann-Louise G , McIntyre Catherine , Siddiqui Aman , Lepori-Bui Nadia , Villar Katlin , Pham Kymhuynh , Bove Rachel , Musa Eric , Reynolds Warren , Kuo Adam , Prabhu Snehit , Rasmussen Lindsey , Cornell Timothy T , Partap Soni , Fisher Paul G , Campen Cynthia J , Grant Gerald , Prolo Laura , Ye Xiaobu , Sahaf Bita , Davis Kara L , Feldman Steven A , Ramakrishna Sneha , Mackall Crystal L 
Published: June 2024

Abstract

BACKGROUND
H3K27M-mutant diffuse midline gliomas (DMGs) express uniformly high levels of the GD2 disialoganglioside. In preclinical models, chimeric antigen receptor modified T-cells (CAR T-cells) targeting GD2 robustly regressed orthotopically xenografted DMGs.

METHODS
This Phase I trial (NCT04196413) administered one IV dose of autologous T-cells transduced with a GD2-CAR retroviral vector to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline gliomas at two dose levels (DL1=1e6 GD2-CAR T-cells/kg; DL2=3e6 GD2-CAR T-cells/kg) following standard lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit following IV infusion were eligible for subsequent intracerebroventricular (ICV) GD2-CAR T-cell infusions (10-30e6 GD2-CAR T-cells). Primary objectives were to determine feasibility of manufacturing, assess tolerability of IV GD2-CAR T-cells in patients with DIPG and sDMG, and identify a maximally tolerated dose of IV GD2-CAR T-cells following lymphodepleting chemotherapy. Secondary objectives included preliminary assessments of benefit. Here we report the final results of Arm A.

RESULTS
Thirteen patients enrolled and 11 received one IV GD2-CAR T infusion on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CAR T-cells were successfully manufactured for each patient. After IV infusion, no dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric reductions of 52%, 54%, 91% and 100%. One patient exhibited a complete response durable for &gt;30 months since therapy began. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score.

CONCLUSIONS
Sequential IV followed by ICV GD2-CAR T-cells infusions induced tumor regressions and neurological improvements. DL1 was established as the maximally tolerated IV GD2-CAR T-cell dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.