Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Abstract

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3-specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase 1 trial employing repeated locoregional B7-H3CARs to children with recurrent/refractory CNS tumors and DIPG. Here, we report results of the first 3 evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3CARs. Targeted mass spectrometry of CSF biospecimens revealed modulation in B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3CAR dosing, and that intracranial delivery may induce local immune activation.

Locoregional CAR T cells for children with CNS tumors: Clinical procedure and catheter safety

“…Specifically, we show the preliminary feasibility of delivering 307 locoregional intracranial infusions to 41 patients across 3 active CNS CAR T cell trials targeting HER2, EGFR, and B7-H3. Delivery through the CNS catheter, whether an Ommaya or shunt reservoir, has been tolerable regardless of the CAR T cell target, which is likely in part to the therapeutic window allotted by our selected targets that are expressed more highly on CNS tumors than normal CNS tissue [15] , [16] , [17] , our manufacturing strategy, and also the streamlined delivery system that we have utilized. Currently, only a select number of pediatric centers have open CAR T cell clinical trials for children with brain and spinal cord tumors.…”

“…Currently, only a select number of pediatric centers have open CAR T cell clinical trials for children with brain and spinal cord tumors. Despite feasibility of intracranial delivery in adult CNS CAR T cell trials [ 14 , 18 ] and preclinical reports of effective and tolerable locoregional delivery to tumor-bearing mice [ 3 , [15] , [16] , [17] , 19 ], there remains a debate in the field regarding the role of systemic versus locoregionally dosed adoptive cellular therapies. Seattle Children's has utilized locoregional CAR T cell delivery on three CAR T cell trials since their activation, and as we continue this therapeutic approach and other programs adopt these systems, it is critical to share early experiences.…”

“…Clinical experience with intracranial CAR T cell dosing [ 14 , 18 ] and preclinical success with locoregional delivery [ 3 , [15] , [16] , [17] , 19 , [27] , [28] , [29] ], led our initial clinical efforts on BrainChild-01 [15] , BrainChild-02, and BrainChild-03 [17] . However, optimal location of intracranial delivery is not yet known and may differ based on age, pathology, prior therapy, and general physiology.…”

“…Based on this preliminary adult experience, the historical success of delivering therapeutics intracranially, and the desire to limit systemic toxicity, Seattle Children's Hospital opened three CNS CAR T cell trials (BrainChild-01 targeting HER2 [15] (NCT03500991), BrainChild-02 targeting EGFR [16] (NCT03638167), and BrainChild-03 targeting B7-H3 [17] (NCT04185038)) that exclusively deploy repeated, locoregional delivery. Across our three phase 1 trials, we have now delivered 307 intracranial CAR T cell doses to 41 children and young adults.…”

Could CAR-T-cell therapy offer hope to children with cancer?

“…Vitanza, for instance, has led trials of three antigen-directed CAR-T-cell products and administered hundreds of cell infusions to more than 60 children. And although the tumour of one young boy with DIPG has been successfully beaten back for more than 14 months and, with infusions every 2 weeks, has no signs of growth, the responses of most children have been much more muted 1 .…”