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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |