Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells
Despite the success of chimeric antigen receptor (CAR) T-cells especially for treating hematological malignancies, critical drawbacks, such as “on-target, off-tumor” toxicities, need to be addressed to improve safety in translating to clinical application. This is especially true, when targeting tum...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-12-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1302354/full |
| _version_ | 1797390276256333824 |
|---|---|
| author | Karla E. G. Soto Liliana R. Loureiro Tabea Bartsch Claudia Arndt Claudia Arndt Alexandra Kegler Nicola Mitwasi Laura Drewitz Lydia Hoffmann Haidy A. Saleh Eugenia Crespo Maria Mehnert Maria Mehnert Cansu Daglar Hinrich Abken Frank Momburg Frank Momburg Michael Bachmann Michael Bachmann Michael Bachmann Michael Bachmann Anja Feldmann Anja Feldmann Anja Feldmann Anja Feldmann |
| author_facet | Karla E. G. Soto Liliana R. Loureiro Tabea Bartsch Claudia Arndt Claudia Arndt Alexandra Kegler Nicola Mitwasi Laura Drewitz Lydia Hoffmann Haidy A. Saleh Eugenia Crespo Maria Mehnert Maria Mehnert Cansu Daglar Hinrich Abken Frank Momburg Frank Momburg Michael Bachmann Michael Bachmann Michael Bachmann Michael Bachmann Anja Feldmann Anja Feldmann Anja Feldmann Anja Feldmann |
| author_sort | Karla E. G. Soto |
| collection | DOAJ |
| description | Despite the success of chimeric antigen receptor (CAR) T-cells especially for treating hematological malignancies, critical drawbacks, such as “on-target, off-tumor” toxicities, need to be addressed to improve safety in translating to clinical application. This is especially true, when targeting tumor-associated antigens (TAAs) that are not exclusively expressed by solid tumors but also on hea9lthy tissues. To improve the safety profile, we developed switchable adaptor CAR systems including the RevCAR system. RevCAR T-cells are activated by cross-linking of bifunctional adaptor molecules termed target modules (RevTM). In a further development, we established a Dual-RevCAR system for an AND-gated combinatorial targeting by splitting the stimulatory and co-stimulatory signals of the RevCAR T-cells on two individual CARs. Examples of common markers for colorectal cancer (CRC) are the carcinoembryonic antigen (CEA) and the epithelial cell adhesion molecule (EpCAM), while these antigens are also expressed by healthy cells. Here we describe four novel structurally different RevTMs for targeting of CEA and EpCAM. All anti-CEA and anti-EpCAM RevTMs were validated and the simultaneous targeting of CEA+ and EpCAM+ cancer cells redirected specific in vitro and in vivo killing by Dual-RevCAR T-cells. In summary, we describe the development of CEA and EpCAM specific adaptor RevTMs for monospecific and AND-gated targeting of CRC cells via the RevCAR platform as an improved approach to increase tumor specificity and safety of CAR T-cell therapies. |
| first_indexed | 2024-03-08T23:08:26Z |
| format | Article |
| id | doaj.art-504decca751c445b97cdaa60cf18debc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-08T23:08:26Z |
| publishDate | 2023-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-504decca751c445b97cdaa60cf18debc2023-12-15T09:05:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-12-011410.3389/fimmu.2023.13023541302354Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cellsKarla E. G. Soto0Liliana R. Loureiro1Tabea Bartsch2Claudia Arndt3Claudia Arndt4Alexandra Kegler5Nicola Mitwasi6Laura Drewitz7Lydia Hoffmann8Haidy A. Saleh9Eugenia Crespo10Maria Mehnert11Maria Mehnert12Cansu Daglar13Hinrich Abken14Frank Momburg15Frank Momburg16Michael Bachmann17Michael Bachmann18Michael Bachmann19Michael Bachmann20Anja Feldmann21Anja Feldmann22Anja Feldmann23Anja Feldmann24Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyMildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyMildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyDepartment of Gene-Immunotherapy, Leibniz-Institute of Immunotherapy, and University Regensburg, Regensburg, GermanyAntigen Presentation and T/NK Cell Activation Group, German Cancer Research Center, Heidelberg, GermanyDepartment of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital, Heidelberg, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyNational Center for Tumor Diseases Dresden (NCT/UCC), partner site Dresden, Dresden, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyGerman Cancer Consortium (DKTK), Partner Site Dresden, Dresden, GermanyInstitute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, GermanyNational Center for Tumor Diseases Dresden (NCT/UCC), partner site Dresden, Dresden, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyGerman Cancer Consortium (DKTK), Partner Site Dresden, Dresden, GermanyDespite the success of chimeric antigen receptor (CAR) T-cells especially for treating hematological malignancies, critical drawbacks, such as “on-target, off-tumor” toxicities, need to be addressed to improve safety in translating to clinical application. This is especially true, when targeting tumor-associated antigens (TAAs) that are not exclusively expressed by solid tumors but also on hea9lthy tissues. To improve the safety profile, we developed switchable adaptor CAR systems including the RevCAR system. RevCAR T-cells are activated by cross-linking of bifunctional adaptor molecules termed target modules (RevTM). In a further development, we established a Dual-RevCAR system for an AND-gated combinatorial targeting by splitting the stimulatory and co-stimulatory signals of the RevCAR T-cells on two individual CARs. Examples of common markers for colorectal cancer (CRC) are the carcinoembryonic antigen (CEA) and the epithelial cell adhesion molecule (EpCAM), while these antigens are also expressed by healthy cells. Here we describe four novel structurally different RevTMs for targeting of CEA and EpCAM. All anti-CEA and anti-EpCAM RevTMs were validated and the simultaneous targeting of CEA+ and EpCAM+ cancer cells redirected specific in vitro and in vivo killing by Dual-RevCAR T-cells. In summary, we describe the development of CEA and EpCAM specific adaptor RevTMs for monospecific and AND-gated targeting of CRC cells via the RevCAR platform as an improved approach to increase tumor specificity and safety of CAR T-cell therapies.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1302354/fullcolorectal cancerCAR T-cellsAND-gate targetingCEAEpCAM |
| spellingShingle | Karla E. G. Soto Liliana R. Loureiro Tabea Bartsch Claudia Arndt Claudia Arndt Alexandra Kegler Nicola Mitwasi Laura Drewitz Lydia Hoffmann Haidy A. Saleh Eugenia Crespo Maria Mehnert Maria Mehnert Cansu Daglar Hinrich Abken Frank Momburg Frank Momburg Michael Bachmann Michael Bachmann Michael Bachmann Michael Bachmann Anja Feldmann Anja Feldmann Anja Feldmann Anja Feldmann Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells Frontiers in Immunology colorectal cancer CAR T-cells AND-gate targeting CEA EpCAM |
| title | Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells |
| title_full | Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells |
| title_fullStr | Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells |
| title_full_unstemmed | Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells |
| title_short | Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells |
| title_sort | targeting colorectal cancer cells using and gated adaptor revcar t cells |
| topic | colorectal cancer CAR T-cells AND-gate targeting CEA EpCAM |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1302354/full |
| work_keys_str_mv | AT karlaegsoto targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT lilianarloureiro targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT tabeabartsch targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT claudiaarndt targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT claudiaarndt targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT alexandrakegler targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT nicolamitwasi targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT lauradrewitz targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT lydiahoffmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT haidyasaleh targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT eugeniacrespo targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT mariamehnert targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT mariamehnert targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT cansudaglar targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT hinrichabken targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT frankmomburg targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT frankmomburg targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT michaelbachmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT michaelbachmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT michaelbachmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT michaelbachmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT anjafeldmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT anjafeldmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT anjafeldmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells AT anjafeldmann targetingcolorectalcancercellsusingandgatedadaptorrevcartcells |