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

Abstract

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.

Authors+Show Affiliations

Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany.Tumor Immunology, University Cancer Center (UCC), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstraβe 74, 01307, Dresden, Germany.Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany.Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany.Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany.Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany.Cellex Patient Treatment GmbH, Tatzberg 47, 01307, Dresden, Germany.GEMoaB Monoclonals GmbH, Tatzberg 47, 01307, Dresden, Germany.Cellex Patient Treatment GmbH, Tatzberg 47, 01307, Dresden, Germany. GEMoaB Monoclonals GmbH, Tatzberg 47, 01307, Dresden, Germany.Medical Clinic and Policlinic I, University Hospital 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstraβe 74, 01307, Dresden, Germany. German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany.Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Bautzner Landstraβe 400, 01328, Dresden, Germany. M.Bachmann@hzdr.de. Tumor Immunology, University Cancer Center (UCC), 'Carl Gustav Carus' Technische Universität Dresden, Fetscherstraβe 74, 01307, Dresden, Germany. M.Bachmann@hzdr.de. German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. M.Bachmann@hzdr.de. National Center for Tumor Diseases (NCT), 'Carl Gustav Carus' Technische Universität Dresden, Dresden, Germany. M.Bachmann@hzdr.de.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31414180

Citation

Koristka, Stefanie, et al. "Anti-CAR-engineered T Cells for Epitope-based Elimination of Autologous CAR T Cells." Cancer Immunology, Immunotherapy : CII, 2019.
Koristka S, Ziller-Walter P, Bergmann R, et al. Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells. Cancer Immunol Immunother. 2019.
Koristka, S., Ziller-Walter, P., Bergmann, R., Arndt, C., Feldmann, A., Kegler, A., ... Bachmann, M. P. (2019). Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells. Cancer Immunology, Immunotherapy : CII, doi:10.1007/s00262-019-02376-y.
Koristka S, et al. Anti-CAR-engineered T Cells for Epitope-based Elimination of Autologous CAR T Cells. Cancer Immunol Immunother. 2019 Aug 14; PubMed PMID: 31414180.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells. AU - Koristka,Stefanie, AU - Ziller-Walter,Pauline, AU - Bergmann,Ralf, AU - Arndt,Claudia, AU - Feldmann,Anja, AU - Kegler,Alexandra, AU - Cartellieri,Marc, AU - Ehninger,Armin, AU - Ehninger,Gerhard, AU - Bornhäuser,Martin, AU - Bachmann,Michael P, Y1 - 2019/08/14/ PY - 2018/09/01/received PY - 2019/08/07/accepted PY - 2019/8/16/entrez KW - Chimeric antigen receptor KW - Elimination tag KW - Immunotherapy KW - Toxicity management JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol. Immunother. N2 - 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. SN - 1432-0851 UR - https://www.unboundmedicine.com/medline/citation/31414180/Anti-CAR-engineered_T_cells_for_epitope-based_elimination_of_autologous_CAR_T_cells L2 - https://dx.doi.org/10.1007/s00262-019-02376-y DB - PRIME DP - Unbound Medicine ER -