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B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres

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...

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Autores principales: Nehama, Dean, Di Ianni, Natalia, Musio, Silvia, Du, Hongwei, Patané, Monica, Pollo, Bianca, Finocchiaro, Gaetano, Park, James J.H., Dunn, Denise E., Edwards, Drake S., Damrauer, Jeffrey S., Hudson, Hannah, Floyd, Scott R., Ferrone, Soldano, Savoldo, Barbara, Pellegatta, Serena, Dotti, Gianpietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796553/
https://www.ncbi.nlm.nih.gov/pubmed/31466914
http://dx.doi.org/10.1016/j.ebiom.2019.08.030
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author Nehama, Dean
Di Ianni, Natalia
Musio, Silvia
Du, Hongwei
Patané, Monica
Pollo, Bianca
Finocchiaro, Gaetano
Park, James J.H.
Dunn, Denise E.
Edwards, Drake S.
Damrauer, Jeffrey S.
Hudson, Hannah
Floyd, Scott R.
Ferrone, Soldano
Savoldo, Barbara
Pellegatta, Serena
Dotti, Gianpietro
author_facet Nehama, Dean
Di Ianni, Natalia
Musio, Silvia
Du, Hongwei
Patané, Monica
Pollo, Bianca
Finocchiaro, Gaetano
Park, James J.H.
Dunn, Denise E.
Edwards, Drake S.
Damrauer, Jeffrey S.
Hudson, Hannah
Floyd, Scott R.
Ferrone, Soldano
Savoldo, Barbara
Pellegatta, Serena
Dotti, Gianpietro
author_sort Nehama, Dean
collection PubMed
description 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: 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: 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: 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.
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spelling pubmed-67965532019-10-22 B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres Nehama, Dean Di Ianni, Natalia Musio, Silvia Du, Hongwei Patané, Monica Pollo, Bianca Finocchiaro, Gaetano Park, James J.H. Dunn, Denise E. Edwards, Drake S. Damrauer, Jeffrey S. Hudson, Hannah Floyd, Scott R. Ferrone, Soldano Savoldo, Barbara Pellegatta, Serena Dotti, Gianpietro EBioMedicine Research paper 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: 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: 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: 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. Elsevier 2019-08-26 /pmc/articles/PMC6796553/ /pubmed/31466914 http://dx.doi.org/10.1016/j.ebiom.2019.08.030 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Nehama, Dean
Di Ianni, Natalia
Musio, Silvia
Du, Hongwei
Patané, Monica
Pollo, Bianca
Finocchiaro, Gaetano
Park, James J.H.
Dunn, Denise E.
Edwards, Drake S.
Damrauer, Jeffrey S.
Hudson, Hannah
Floyd, Scott R.
Ferrone, Soldano
Savoldo, Barbara
Pellegatta, Serena
Dotti, Gianpietro
B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title_full B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title_fullStr B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title_full_unstemmed B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title_short B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres
title_sort b7-h3-redirected chimeric antigen receptor t cells target glioblastoma and neurospheres
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796553/
https://www.ncbi.nlm.nih.gov/pubmed/31466914
http://dx.doi.org/10.1016/j.ebiom.2019.08.030
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