Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers
Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using tim...
| Autores: | , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2022 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/69001 |
| Acesso em linha: | https://hdl.handle.net/10171/69001 |
| Access Level: | acceso abierto |
| Palavra-chave: | Colon organoids T-cell engager Colon cancer Live confocal microscopy |
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Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagersTeijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30Miguéliz-Basterra, I. (Itziar)|||/items/f8b05fe5-028a-4ebf-a3d8-bff420f4b61dGarasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713Karanikas, V. (Vaios)|||/items/20e0c47b-08f9-423a-b7dc-f51eaacc46e0Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8dCirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790Rodriguez-Ruiz, M.E. (María Esperanza)|||/items/bb89f8c4-6380-4de3-8dd0-877dbf28ef44Colon organoidsT-cell engagerColon cancerLive confocal microscopyRationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.Dadun. Depósito Académico Digital Universidad de Navarra20242024-02-0920222022-01-0120222022-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/69001reponame:Dadun. Depósito Académico Digital de la Universidad de Navarrainstname:Universidad de NavarraInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:dadun.unav.edu:10171/690012026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| title |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| spellingShingle |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Colon organoids T-cell engager Colon cancer Live confocal microscopy |
| title_short |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| title_full |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| title_fullStr |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| title_full_unstemmed |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| title_sort |
Three-dimensional colon cancer organoids model the response to CEA-CD3 T-cell engagers |
| dc.creator.none.fl_str_mv |
Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Miguéliz-Basterra, I. (Itziar)|||/items/f8b05fe5-028a-4ebf-a3d8-bff420f4b61d Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Karanikas, V. (Vaios)|||/items/20e0c47b-08f9-423a-b7dc-f51eaacc46e0 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 Rodriguez-Ruiz, M.E. (María Esperanza)|||/items/bb89f8c4-6380-4de3-8dd0-877dbf28ef44 |
| author |
Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 |
| author_facet |
Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Miguéliz-Basterra, I. (Itziar)|||/items/f8b05fe5-028a-4ebf-a3d8-bff420f4b61d Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Karanikas, V. (Vaios)|||/items/20e0c47b-08f9-423a-b7dc-f51eaacc46e0 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 Rodriguez-Ruiz, M.E. (María Esperanza)|||/items/bb89f8c4-6380-4de3-8dd0-877dbf28ef44 |
| author_role |
author |
| author2 |
Miguéliz-Basterra, I. (Itziar)|||/items/f8b05fe5-028a-4ebf-a3d8-bff420f4b61d Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Karanikas, V. (Vaios)|||/items/20e0c47b-08f9-423a-b7dc-f51eaacc46e0 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 Rodriguez-Ruiz, M.E. (María Esperanza)|||/items/bb89f8c4-6380-4de3-8dd0-877dbf28ef44 |
| author2_role |
author author author author author author |
| dc.contributor.none.fl_str_mv |
Dadun. Depósito Académico Digital Universidad de Navarra |
| dc.subject.none.fl_str_mv |
Colon organoids T-cell engager Colon cancer Live confocal microscopy |
| topic |
Colon organoids T-cell engager Colon cancer Live confocal microscopy |
| description |
Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFNγ and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system. |
| publishDate |
2022 |
| dc.date.none.fl_str_mv |
2022 2022-01-01 2022 2022-01-01 2024 2024-02-09 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/10171/69001 |
| url |
https://hdl.handle.net/10171/69001 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 |
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info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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application/pdf |
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reponame:Dadun. Depósito Académico Digital de la Universidad de Navarra instname:Universidad de Navarra |
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Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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Dadun. Depósito Académico Digital de la Universidad de Navarra |
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15.301603 |