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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2019
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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. |
format | Online Article Text |
id | pubmed-6768917 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
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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