Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis
Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of mon...
| Autores: | , , , , , , , , , |
|---|---|
| Tipo de documento: | artigo |
| Data de publicação: | 2021 |
| País: | España |
| Recursos: | Universidad de Navarra |
| Repositório: | Dadun. Depósito Académico Digital de la Universidad de Navarra |
| Idioma: | inglês |
| OAI Identifier: | oai:dadun.unav.edu:10171/115134 |
| Acesso em linha: | https://hdl.handle.net/10171/115134 |
| Access Level: | Acceso aberto |
| Palavra-chave: | PD-L1 Adenovirus Clodronate Colorectal cancer Drug-inducible system High-capacity adenoviral vector Immune checkpoint inhibitor Macrophages Mifepristone Peritoneal carcinomatosis |
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Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosisBuñuales, M. (María)|||/items/80f24424-99e3-421f-9398-c067c56bf099Ballesteros-Briones, M.C. (María Cristina)|||/items/4ede3e7d-1b82-4945-a24c-a96d8e2dff71Gonzalez-Aparicio, M. (Manuela)|||/items/5d489890-239c-4227-8485-16049b53502eHervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8fEva Martisova |||/items/80cb8569-6236-4f78-b528-c3d5bfc8efdeMancheño, U. (Uxua)|||/items/7e9b5aee-3e45-40fb-b87f-19be6c19dd6cRicobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924abLumbreras, S. (Sara)|||/items/a25d12b6-a452-41b1-835b-ccc8b653c31cSmerdou-Picazo, C. (Cristian)|||/items/48fd1bd4-6483-45c9-9951-8a1b04873227Hernández-Alcoceba, R. (Rubén)|||/items/c10dc855-ee3e-41a7-a4cf-2783e1a36f5ePD-L1AdenovirusClodronateColorectal cancerDrug-inducible systemHigh-capacity adenoviral vectorImmune checkpoint inhibitorMacrophagesMifepristonePeritoneal carcinomatosisImmune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.MDPIDadun. Depósito Académico Digital Universidad de Navarra20212021-01-0120212021-01-01journal articlehttp://purl.org/coar/resource_type/c_6501info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/10171/115134reponame: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:10171/1151342026-06-21T12:47:57Z |
| dc.title.none.fl_str_mv |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| title |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| spellingShingle |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis Buñuales, M. (María)|||/items/80f24424-99e3-421f-9398-c067c56bf099 PD-L1 Adenovirus Clodronate Colorectal cancer Drug-inducible system High-capacity adenoviral vector Immune checkpoint inhibitor Macrophages Mifepristone Peritoneal carcinomatosis |
| title_short |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| title_full |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| title_fullStr |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| title_full_unstemmed |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| title_sort |
Adenovirus-mediated inducible expression of a PD-L1 blocking antibody in combination with macrophage depletion improves survival in a mouse model of peritoneal carcinomatosis |
| dc.creator.none.fl_str_mv |
Buñuales, M. (María)|||/items/80f24424-99e3-421f-9398-c067c56bf099 Ballesteros-Briones, M.C. (María Cristina)|||/items/4ede3e7d-1b82-4945-a24c-a96d8e2dff71 Gonzalez-Aparicio, M. (Manuela)|||/items/5d489890-239c-4227-8485-16049b53502e Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f Eva Martisova |||/items/80cb8569-6236-4f78-b528-c3d5bfc8efde Mancheño, U. (Uxua)|||/items/7e9b5aee-3e45-40fb-b87f-19be6c19dd6c Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Lumbreras, S. (Sara)|||/items/a25d12b6-a452-41b1-835b-ccc8b653c31c Smerdou-Picazo, C. (Cristian)|||/items/48fd1bd4-6483-45c9-9951-8a1b04873227 Hernández-Alcoceba, R. (Rubén)|||/items/c10dc855-ee3e-41a7-a4cf-2783e1a36f5e |
| author |
Buñuales, M. (María)|||/items/80f24424-99e3-421f-9398-c067c56bf099 |
| author_facet |
Buñuales, M. (María)|||/items/80f24424-99e3-421f-9398-c067c56bf099 Ballesteros-Briones, M.C. (María Cristina)|||/items/4ede3e7d-1b82-4945-a24c-a96d8e2dff71 Gonzalez-Aparicio, M. (Manuela)|||/items/5d489890-239c-4227-8485-16049b53502e Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f Eva Martisova |||/items/80cb8569-6236-4f78-b528-c3d5bfc8efde Mancheño, U. (Uxua)|||/items/7e9b5aee-3e45-40fb-b87f-19be6c19dd6c Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Lumbreras, S. (Sara)|||/items/a25d12b6-a452-41b1-835b-ccc8b653c31c Smerdou-Picazo, C. (Cristian)|||/items/48fd1bd4-6483-45c9-9951-8a1b04873227 Hernández-Alcoceba, R. (Rubén)|||/items/c10dc855-ee3e-41a7-a4cf-2783e1a36f5e |
| author_role |
author |
| author2 |
Ballesteros-Briones, M.C. (María Cristina)|||/items/4ede3e7d-1b82-4945-a24c-a96d8e2dff71 Gonzalez-Aparicio, M. (Manuela)|||/items/5d489890-239c-4227-8485-16049b53502e Hervas-Stubbs, S. (Sandra)|||/items/8f56cb52-4465-4428-8acf-e50439c6be8f Eva Martisova |||/items/80cb8569-6236-4f78-b528-c3d5bfc8efde Mancheño, U. (Uxua)|||/items/7e9b5aee-3e45-40fb-b87f-19be6c19dd6c Ricobaraza, A. (Ana)|||/items/a537e067-03df-4041-b520-0d8a5bd924ab Lumbreras, S. (Sara)|||/items/a25d12b6-a452-41b1-835b-ccc8b653c31c Smerdou-Picazo, C. (Cristian)|||/items/48fd1bd4-6483-45c9-9951-8a1b04873227 Hernández-Alcoceba, R. (Rubén)|||/items/c10dc855-ee3e-41a7-a4cf-2783e1a36f5e |
| author2_role |
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 |
PD-L1 Adenovirus Clodronate Colorectal cancer Drug-inducible system High-capacity adenoviral vector Immune checkpoint inhibitor Macrophages Mifepristone Peritoneal carcinomatosis |
| topic |
PD-L1 Adenovirus Clodronate Colorectal cancer Drug-inducible system High-capacity adenoviral vector Immune checkpoint inhibitor Macrophages Mifepristone Peritoneal carcinomatosis |
| description |
Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer. |
| publishDate |
2021 |
| dc.date.none.fl_str_mv |
2021 2021-01-01 2021 2021-01-01 |
| 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/10171/115134 |
| url |
https://hdl.handle.net/10171/115134 |
| 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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MDPI |
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MDPI |
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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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15.812455 |