41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo

Background Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapi...

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Detalles Bibliográficos
Autores: Libero Baroni, Matteo, Anguita Mandly, Eduardo Luis, Menéndez, Pablo
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/117554
Acceso en línea:https://hdl.handle.net/20.500.14352/117554
Access Level:acceso abierto
Palabra clave:616.15
T lymphocytes
cell engineering
immunotherapy
adoptive
Hematología
3205.04 Hematología
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oai_identifier_str oai:docta.ucm.es:20.500.14352/117554
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spelling 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivoLibero Baroni, MatteoAnguita Mandly, Eduardo LuisMenéndez, Pablo616.15T lymphocytescell engineeringimmunotherapyadoptiveHematología3205.04 HematologíaBackground Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. Methods We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. Results Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. Conclusions This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.BMJ Publishing Group Ltd.Universidad Complutense de Madrid20202020-01-0120202020-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/117554reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1175542026-06-02T12:44:21Z
dc.title.none.fl_str_mv 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
title 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
spellingShingle 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
Libero Baroni, Matteo
616.15
T lymphocytes
cell engineering
immunotherapy
adoptive
Hematología
3205.04 Hematología
title_short 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
title_full 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
title_fullStr 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
title_full_unstemmed 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
title_sort 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
dc.creator.none.fl_str_mv Libero Baroni, Matteo
Anguita Mandly, Eduardo Luis
Menéndez, Pablo
author Libero Baroni, Matteo
author_facet Libero Baroni, Matteo
Anguita Mandly, Eduardo Luis
Menéndez, Pablo
author_role author
author2 Anguita Mandly, Eduardo Luis
Menéndez, Pablo
author2_role author
author
dc.contributor.none.fl_str_mv Universidad Complutense de Madrid
dc.subject.none.fl_str_mv 616.15
T lymphocytes
cell engineering
immunotherapy
adoptive
Hematología
3205.04 Hematología
topic 616.15
T lymphocytes
cell engineering
immunotherapy
adoptive
Hematología
3205.04 Hematología
description Background Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative. Methods We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs. Results Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs. Conclusions This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.14352/117554
url https://hdl.handle.net/20.500.14352/117554
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group Ltd.
publisher.none.fl_str_mv BMJ Publishing Group Ltd.
dc.source.none.fl_str_mv reponame:Docta Complutense
instname:Universidad Complutense de Madrid (UCM)
instname_str Universidad Complutense de Madrid (UCM)
reponame_str Docta Complutense
collection Docta Complutense
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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