TRLS-05. PRELIMINARY RESULTS FROM A PHASE I TRIAL TO EVALUATE INTRAVENTRICULAR DELIVERY OF IL13RΑ2-TARGETING CAR T CELLS AFTER LYMPHODEPLETION IN PEDIATRIC BRAIN TUMORS PATIENTS

Abstract

Abstract Brain tumors are the leading cause of cancer death in children, and outcomes for patients with recurrent or aggressive disease remain poor. We have previously shown that locoregionally-delivered chimeric antigen receptor (CAR) T cells targeting the high-affinity IL13 receptor IL13Rα2 are safe and well-tolerated in adults, and that they can mediate a remarkable clinical response. This antigen is also expressed on roughly half of pediatric neuromalignancies. Here, we present the clinical experience from the first patients treated with IL13BBζ-CAR T cells on our trial. Patients received four doses of CAR T cells, delivered weekly through an indwelling CNS catheter; the first dose was 1e7 CAR T cells and subsequent doses were 5e7 cells. The first three patients received CAR T cells alone; the rest received lymphodepletion with cyclophosphamide and fludarabine before CAR T cell infusion. After follow-up imaging at the end of the dose-limiting toxicity (DLT) period, patients were given the option to continue therapy. Six patients have been treated without DLTs; one patient on the lymphodepletion arm did not complete the four infusions due to a Grade 3 catheter-related infection. Other patients experienced occasional Grade 3 AEs that were not attributed to CAR T therapy, with the exception of headache, muscle weakness, and ALT elevation. Otherwise, AEs were Grade 1-2. Five patients completed four infusions and were evaluable at the end of the DLT period. Of those, three experienced radiographic and/or clinical benefit, although none met protocol criteria for a partial response. Specific cytokines were increased in the cerebrospinal fluid (CSF) of patients during radiographic response periods. Additionally, single-cell transcriptomic analysis paired with TCR sequencing of CSF cells demonstrated characteristic immune signatures correlated with response. These preliminary results support combining lymphodepletion and repeated intraventricular CAR T cell delivery as a promising therapy in children with brain tumors.