B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres.
Animals
Antigens, Neoplasm
/ immunology
B7 Antigens
/ genetics
Biomarkers
Brain Neoplasms
/ immunology
Cell Line, Tumor
Disease Models, Animal
Glioblastoma
/ immunology
Humans
Immunophenotyping
Immunotherapy, Adoptive
Mice
Neoplastic Stem Cells
/ immunology
Receptors, Antigen, T-Cell
/ metabolism
Receptors, Chimeric Antigen
/ metabolism
T-Lymphocytes
/ immunology
Xenograft Model Antitumor Assays
B7-H3
Cancer stem cells
Chimeric antigen receptor
Glioblastoma
Immunotherapy
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Sep 2019
Sep 2019
Historique:
received:
11
06
2019
revised:
13
08
2019
accepted:
14
08
2019
pubmed:
31
8
2019
medline:
12
2
2020
entrez:
31
8
2019
Statut:
ppublish
Résumé
The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM. We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models. B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines. We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. FUND: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund.
Sections du résumé
BACKGROUND
BACKGROUND
The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM.
METHODS
METHODS
We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models.
FINDINGS
RESULTS
B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines.
INTERPRETATION
CONCLUSIONS
We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. FUND: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund.
Identifiants
pubmed: 31466914
pii: S2352-3964(19)30552-3
doi: 10.1016/j.ebiom.2019.08.030
pmc: PMC6796553
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
B7 Antigens
0
Biomarkers
0
CD276 protein, human
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
33-43Subventions
Organisme : NCI NIH HHS
ID : R03 CA231766
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA226483
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA223886
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008719
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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