ID #1113 Low dose intravenous autologous third generation GD2-CAR-T cell therapy in diffuse midline glioma patients: anti-tumour activity with minimal toxicity
Neevika Manoharan, Tessa Gargett, Sidra Khan, Erica Yeo, Nga Truong, Bryan Gardam, Orazio Vittorio, Maria Tsoli, Tyler Shai-Hee, Rob Salomon, Chelsea Mayoh, Wenyan Li, Lisa Ebert, Sekhar Pillai, Erica Jacobson, Lily Wong, Laura Mitchell, Marion Mateos, Roslyn Avard, Annette Trickett, Adam Nelson, Richard Mitchell, Michelle Monje, Michael Brown, David ZieglerAbstract
Chimeric antigen receptor T (CAR T) cells are a promising therapeutic strategy for the clinical management of diffuse midline glioma (DMG), the most aggressive paediatric brain cancer. Here, we report the first three patients with DMG treated in an ongoing phase 1 clinical trial of autologous GD2-specific CAR-T therapy. The GD2-CAR-T product under investigation features a distinct design with third-generation (14g2a.OX40.CD28.zeta) signalling and, in contrast to previous studies, is administered in combination with anti-VEGF therapy (bevacizumab) to counteract potential oedema from on-target, on-tumour CAR-T effects after lymphodepleting chemotherapy (fludarabine/cyclophosphamide).
Two of the three patients who received an intravenous infusion at a low initial dose (0.3 million cells/kg) demonstrated tumour volume reductions exceeding 50%, without the severe hyperinflammation seen with other CAR-T cell therapies. Sustained radiological responses correlated with objective neurological improvements in these patients (one thalamic and one pontine DMG). No dose-limiting toxicities (DLTs) were observed at dose level 1 (DL1), and there were no grade 3–4 events of cytokine release syndrome (CRS) or tumour inflammation–associated neuropathy (TIAN). Patients who exhibited tumour responses showed distinct proteomic signatures associated with T-cell activation and recruitment, including elevated plasma and cerebrospinal fluid (CSF) granzyme B, while the patient with progressive disease had a proteomic signature suggesting little immune engagement. Our results indicate anti-tumour activity of IV low-dose third-generation GD2-CAR-T administered with anti-VEGF therapy after radiotherapy. Dose escalation continues in the ongoing trial and this will further investigate regimen safety, efficacy and help determine the optimal therapeutic dose.