Dataset Information

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 I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three 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-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.

Significance

This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF. This article is highlighted in the In This Issue feature, p. 1.

SUBMITTER: Vitanza NA

PROVIDER: S-EPMC9827115 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Vitanza Nicholas A NA Wilson Ashley L AL Huang Wenjun W Seidel Kristy K Brown Christopher C Gustafson Joshua A JA Yokoyama Jason K JK Johnson Adam J AJ Baxter Blake A BA Koning Ryan W RW Reid Aquene N AN Meechan Michael M Biery Matthew C MC Myers Carrie C Rawlings-Rhea Stephanie D SD Albert Catherine M CM Browd Samuel R SR Hauptman Jason S JS Lee Amy A Ojemann Jeffrey G JG Berens Michael E ME Dun Matthew D MD Foster Jessica B JB Crotty Erin E EE Leary Sarah E S SES Cole Bonnie L BL Perez Francisco A FA Wright Jason N JN Orentas Rimas J RJ Chour Tony T Newell Evan W EW Whiteaker Jeffrey R JR Zhao Lei L Paulovich Amanda G AG Pinto Navin N Gust Juliane J Gardner Rebecca A RA Jensen Michael C MC Park Julie R JR

Cancer discovery 20230101 1

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 I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the f ...[more]

PMID: 36259971

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Project description:Abstract Considering the high expression of B7-H3 (CD276) on diffuse intrinsic pontine glioma (DIPG) and preliminary evidence that repeated locoregional delivery of CAR T cells to patients with CNS tumors was feasible and tolerable, we open the phase 1 trial BrainChild-03 (NCT04185038). Children with DIPG in Dose Regimen 1 received 40 intraventricular B7H3CAR doses, with the two patients enrolling post-progression surviving >400 days from initial CAR T infusion. To evaluate for immune and tumor responses that may correlate with clinical and radiographic evaluations, we performed targeted proteomic analysis on serial CSF and serum biospecimens. MRM-MS is a targeted mass spectrometry that provides sensitive measurement of proteins in cancer tissues and fluids. In 2 patients with longitudinal biospecimens, we identified 50 CSF and 59 serum proteins above level of detection. In general, there were fewer serum fluctuations compared to the CSF, supporting that intracranial delivery provides local immune activation. Sharp fluctuations of several immunoregulatory peptides were measured in the CSF at pre and post infusion timepoints, including BCL10, CXCL13, TIM-3, ICOSLG, and PD-L2. Notably, several analytes tracked consistently in the CSF of both patients, including markers of macrophage maturation and immune cell recruitment, including CD14, CD163, CD44, CSF-1, CXCL13 and VCAM-1. B7-H3 was detected in the CSF and serum of both patients. S005, who progressed on protocol therapy, had a sharp increase in B7-H3 in the CSF during Course 2, while S008, who had clinical improvement on protocol therapy, had consistently lower B7-H3 present. Notably, serum B7-H3 steadily declined in both patients over time, with the exception of a transient increase in S005 between Courses 4 and 5. Future work for all enrolled patients with DIPG will explore the correlation of these targeted proteomic measurements with clinical end points for potential use as markers of efficacy of therapy or adverse events.

Dataset Information

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

Significance

Publications

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

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