Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists
Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to...
| Autores: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Navarra |
| Repositorio: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglés |
| OAI Identifier: | oai:dadun.unav.edu:10171/67856 |
| Acceso en línea: | https://hdl.handle.net/10171/67856 |
| Access Level: | acceso abierto |
| Palabra clave: | 4-1BB CD137 IL-12 MT: Delivery Strategies TGF-β Local immunotherapy mRNA |
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Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonistsCirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8dDi-Trani, C.A. (Claudia Augusta)|||/items/5d899126-779d-4c97-8232-95bfe18f9f26Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1Gomis-Cobos, G. (Gabriel)|||/items/c756710a-4f47-4acf-a13a-b47c739cef8cPinci, B. (Beatrice)|||/items/319d608a-6b4d-4209-9582-8cdabd7f017cGarasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5eAzpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644eValencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51fPalencia-Coto, B. (Belén)|||/items/c439a2a6-fad9-4a0b-8309-ceca8c25edf2Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4eGonzález-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b764-1BBCD137IL-12MT: Delivery StrategiesTGF-βLocal immunotherapymRNAIntratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor b (TGF-b) and CD137 (4-1BB). Several neutralizing TGF- b agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-beta and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade.Dadun. Depósito Académico Digital Universidad de Navarra20232023-11-1520232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/67856reponame: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:10171/678562026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| title |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| spellingShingle |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 4-1BB CD137 IL-12 MT: Delivery Strategies TGF-β Local immunotherapy mRNA |
| title_short |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| title_full |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| title_fullStr |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| title_full_unstemmed |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| title_sort |
Intratumoral immunotherapy with mRNAs encoding chimeric protein constructs encompassing IL-12, CD137 agonists, and TGF-ß antagonists |
| dc.creator.none.fl_str_mv |
Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Di-Trani, C.A. (Claudia Augusta)|||/items/5d899126-779d-4c97-8232-95bfe18f9f26 Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1 Gomis-Cobos, G. (Gabriel)|||/items/c756710a-4f47-4acf-a13a-b47c739cef8c Pinci, B. (Beatrice)|||/items/319d608a-6b4d-4209-9582-8cdabd7f017c Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5e Azpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9 Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644e Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f Palencia-Coto, B. (Belén)|||/items/c439a2a6-fad9-4a0b-8309-ceca8c25edf2 Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781 Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89 Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76 |
| author |
Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 |
| author_facet |
Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790 Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Di-Trani, C.A. (Claudia Augusta)|||/items/5d899126-779d-4c97-8232-95bfe18f9f26 Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1 Gomis-Cobos, G. (Gabriel)|||/items/c756710a-4f47-4acf-a13a-b47c739cef8c Pinci, B. (Beatrice)|||/items/319d608a-6b4d-4209-9582-8cdabd7f017c Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5e Azpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9 Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644e Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f Palencia-Coto, B. (Belén)|||/items/c439a2a6-fad9-4a0b-8309-ceca8c25edf2 Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781 Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89 Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76 |
| author_role |
author |
| author2 |
Bolaños-Mateo, E. (Elixabet)|||/items/073a1977-5579-4bd1-8604-98b3ccfd4361 Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d Di-Trani, C.A. (Claudia Augusta)|||/items/5d899126-779d-4c97-8232-95bfe18f9f26 Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1 Gomis-Cobos, G. (Gabriel)|||/items/c756710a-4f47-4acf-a13a-b47c739cef8c Pinci, B. (Beatrice)|||/items/319d608a-6b4d-4209-9582-8cdabd7f017c Garasa, S. (Saray)|||/items/51924af8-57aa-477c-b3d8-886422be3713 Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5e Azpilikueta, A. (Arantza)|||/items/8cb8f9c3-bb52-41cc-a19d-03de632308e9 Eguren-Santamaría, I. (Iñaki)|||/items/a597d707-9f63-46ab-8da1-e99ed05e644e Valencia, K. (Karmele)|||/items/bf771eab-81c1-4221-80f5-87713ad5e51f Palencia-Coto, B. (Belén)|||/items/c439a2a6-fad9-4a0b-8309-ceca8c25edf2 Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781 Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89 Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30 Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91 Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e González-Vaz, J. (Javier)|||/items/9d321bb0-f713-4608-8d35-15b1c9588b76 |
| author2_role |
author author author author author author author author author author author author 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 |
4-1BB CD137 IL-12 MT: Delivery Strategies TGF-β Local immunotherapy mRNA |
| topic |
4-1BB CD137 IL-12 MT: Delivery Strategies TGF-β Local immunotherapy mRNA |
| description |
Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor b (TGF-b) and CD137 (4-1BB). Several neutralizing TGF- b agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-beta and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-11-15 2023 2023-01-01 2023 2023-01-01 |
| 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/10171/67856 |
| url |
https://hdl.handle.net/10171/67856 |
| 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 |
| dc.format.none.fl_str_mv |
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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15,300724 |