Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
09 01 2023
09 01 2023
Historique:
received:
13
07
2022
revised:
13
09
2022
accepted:
13
10
2022
pubmed:
20
10
2022
medline:
11
1
2023
entrez:
19
10
2022
Statut:
ppublish
Résumé
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. 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.
Identifiants
pubmed: 36259971
pii: 709786
doi: 10.1158/2159-8290.CD-22-0750
pmc: PMC9827115
mid: NIHMS1844899
doi:
Substances chimiques
B7 Antigens
0
CD276 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
114-131Subventions
Organisme : NCI NIH HHS
ID : R01 CA235575
Pays : United States
Organisme : NCATS NIH HHS
ID : U01 TR002487
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201500003C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201500003I
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214114
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA271407
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211499
Pays : United States
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
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