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Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells

Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated...

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Autores principales: Koristka, Stefanie, Ziller-Walter, Pauline, Bergmann, Ralf, Arndt, Claudia, Feldmann, Anja, Kegler, Alexandra, Cartellieri, Marc, Ehninger, Armin, Ehninger, Gerhard, Bornhäuser, Martin, Bachmann, Michael P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768917/
https://www.ncbi.nlm.nih.gov/pubmed/31414180
http://dx.doi.org/10.1007/s00262-019-02376-y
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author Koristka, Stefanie
Ziller-Walter, Pauline
Bergmann, Ralf
Arndt, Claudia
Feldmann, Anja
Kegler, Alexandra
Cartellieri, Marc
Ehninger, Armin
Ehninger, Gerhard
Bornhäuser, Martin
Bachmann, Michael P.
author_facet Koristka, Stefanie
Ziller-Walter, Pauline
Bergmann, Ralf
Arndt, Claudia
Feldmann, Anja
Kegler, Alexandra
Cartellieri, Marc
Ehninger, Armin
Ehninger, Gerhard
Bornhäuser, Martin
Bachmann, Michael P.
author_sort Koristka, Stefanie
collection PubMed
description Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients’ immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-019-02376-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-67689172019-10-16 Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells Koristka, Stefanie Ziller-Walter, Pauline Bergmann, Ralf Arndt, Claudia Feldmann, Anja Kegler, Alexandra Cartellieri, Marc Ehninger, Armin Ehninger, Gerhard Bornhäuser, Martin Bachmann, Michael P. Cancer Immunol Immunother Original Article Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients’ immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00262-019-02376-y) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2019-08-14 2019 /pmc/articles/PMC6768917/ /pubmed/31414180 http://dx.doi.org/10.1007/s00262-019-02376-y Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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.
spellingShingle Original Article
Koristka, Stefanie
Ziller-Walter, Pauline
Bergmann, Ralf
Arndt, Claudia
Feldmann, Anja
Kegler, Alexandra
Cartellieri, Marc
Ehninger, Armin
Ehninger, Gerhard
Bornhäuser, Martin
Bachmann, Michael P.
Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title_full Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title_fullStr Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title_full_unstemmed Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title_short Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
title_sort anti-car-engineered t cells for epitope-based elimination of autologous car t cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768917/
https://www.ncbi.nlm.nih.gov/pubmed/31414180
http://dx.doi.org/10.1007/s00262-019-02376-y
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