Cargando…

A modular and controllable T cell therapy platform for acute myeloid leukemia

Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the g...

Descripción completa

Detalles Bibliográficos
Autores principales: Benmebarek, Mohamed-Reda, Cadilha, Bruno L., Herrmann, Monika, Lesch, Stefanie, Schmitt, Saskia, Stoiber, Stefan, Darwich, Abbass, Augsberger, Christian, Brauchle, Bettina, Rohrbacher, Lisa, Oner, Arman, Seifert, Matthias, Schwerdtfeger, Melanie, Gottschlich, Adrian, Rataj, Felicitas, Fenn, Nadja C., Klein, Christian, Subklewe, Marion, Endres, Stefan, Hopfner, Karl-Peter, Kobold, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789085/
https://www.ncbi.nlm.nih.gov/pubmed/33414484
http://dx.doi.org/10.1038/s41375-020-01109-w
_version_ 1783633163440881664
author Benmebarek, Mohamed-Reda
Cadilha, Bruno L.
Herrmann, Monika
Lesch, Stefanie
Schmitt, Saskia
Stoiber, Stefan
Darwich, Abbass
Augsberger, Christian
Brauchle, Bettina
Rohrbacher, Lisa
Oner, Arman
Seifert, Matthias
Schwerdtfeger, Melanie
Gottschlich, Adrian
Rataj, Felicitas
Fenn, Nadja C.
Klein, Christian
Subklewe, Marion
Endres, Stefan
Hopfner, Karl-Peter
Kobold, Sebastian
author_facet Benmebarek, Mohamed-Reda
Cadilha, Bruno L.
Herrmann, Monika
Lesch, Stefanie
Schmitt, Saskia
Stoiber, Stefan
Darwich, Abbass
Augsberger, Christian
Brauchle, Bettina
Rohrbacher, Lisa
Oner, Arman
Seifert, Matthias
Schwerdtfeger, Melanie
Gottschlich, Adrian
Rataj, Felicitas
Fenn, Nadja C.
Klein, Christian
Subklewe, Marion
Endres, Stefan
Hopfner, Karl-Peter
Kobold, Sebastian
author_sort Benmebarek, Mohamed-Reda
collection PubMed
description Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33(+) and CD123(+) AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.
format Online
Article
Text
id pubmed-7789085
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-77890852021-01-08 A modular and controllable T cell therapy platform for acute myeloid leukemia Benmebarek, Mohamed-Reda Cadilha, Bruno L. Herrmann, Monika Lesch, Stefanie Schmitt, Saskia Stoiber, Stefan Darwich, Abbass Augsberger, Christian Brauchle, Bettina Rohrbacher, Lisa Oner, Arman Seifert, Matthias Schwerdtfeger, Melanie Gottschlich, Adrian Rataj, Felicitas Fenn, Nadja C. Klein, Christian Subklewe, Marion Endres, Stefan Hopfner, Karl-Peter Kobold, Sebastian Leukemia Article Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33(+) and CD123(+) AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment. Nature Publishing Group UK 2021-01-07 2021 /pmc/articles/PMC7789085/ /pubmed/33414484 http://dx.doi.org/10.1038/s41375-020-01109-w Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Benmebarek, Mohamed-Reda
Cadilha, Bruno L.
Herrmann, Monika
Lesch, Stefanie
Schmitt, Saskia
Stoiber, Stefan
Darwich, Abbass
Augsberger, Christian
Brauchle, Bettina
Rohrbacher, Lisa
Oner, Arman
Seifert, Matthias
Schwerdtfeger, Melanie
Gottschlich, Adrian
Rataj, Felicitas
Fenn, Nadja C.
Klein, Christian
Subklewe, Marion
Endres, Stefan
Hopfner, Karl-Peter
Kobold, Sebastian
A modular and controllable T cell therapy platform for acute myeloid leukemia
title A modular and controllable T cell therapy platform for acute myeloid leukemia
title_full A modular and controllable T cell therapy platform for acute myeloid leukemia
title_fullStr A modular and controllable T cell therapy platform for acute myeloid leukemia
title_full_unstemmed A modular and controllable T cell therapy platform for acute myeloid leukemia
title_short A modular and controllable T cell therapy platform for acute myeloid leukemia
title_sort modular and controllable t cell therapy platform for acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789085/
https://www.ncbi.nlm.nih.gov/pubmed/33414484
http://dx.doi.org/10.1038/s41375-020-01109-w
work_keys_str_mv AT benmebarekmohamedreda amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT cadilhabrunol amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT herrmannmonika amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT leschstefanie amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT schmittsaskia amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT stoiberstefan amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT darwichabbass amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT augsbergerchristian amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT brauchlebettina amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT rohrbacherlisa amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT onerarman amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT seifertmatthias amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT schwerdtfegermelanie amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT gottschlichadrian amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT ratajfelicitas amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT fennnadjac amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT kleinchristian amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT subklewemarion amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT endresstefan amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT hopfnerkarlpeter amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT koboldsebastian amodularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT benmebarekmohamedreda modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT cadilhabrunol modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT herrmannmonika modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT leschstefanie modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT schmittsaskia modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT stoiberstefan modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT darwichabbass modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT augsbergerchristian modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT brauchlebettina modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT rohrbacherlisa modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT onerarman modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT seifertmatthias modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT schwerdtfegermelanie modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT gottschlichadrian modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT ratajfelicitas modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT fennnadjac modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT kleinchristian modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT subklewemarion modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT endresstefan modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT hopfnerkarlpeter modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia
AT koboldsebastian modularandcontrollabletcelltherapyplatformforacutemyeloidleukemia