Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Buñuales, Maria, Ballesteros-Briones, Maria Cristina, Gonzalez-Aparicio, Manuela, Hervas-Stubbs, Sandra, Martisova, Eva, Mancheño, Uxua, Ricobaraza, Ana, Lumbreras, Sara, Smerdou, Cristian, Hernandez-Alcoceba, Ruben
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073765/
https://www.ncbi.nlm.nih.gov/pubmed/33920699
http://dx.doi.org/10.3390/ijms22084176
_version_ 1783684205354418176
author Buñuales, Maria
Ballesteros-Briones, Maria Cristina
Gonzalez-Aparicio, Manuela
Hervas-Stubbs, Sandra
Martisova, Eva
Mancheño, Uxua
Ricobaraza, Ana
Lumbreras, Sara
Smerdou, Cristian
Hernandez-Alcoceba, Ruben
author_facet Buñuales, Maria
Ballesteros-Briones, Maria Cristina
Gonzalez-Aparicio, Manuela
Hervas-Stubbs, Sandra
Martisova, Eva
Mancheño, Uxua
Ricobaraza, Ana
Lumbreras, Sara
Smerdou, Cristian
Hernandez-Alcoceba, Ruben
author_sort Buñuales, Maria
collection PubMed
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.
format Online
Article
Text
id pubmed-8073765
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-80737652021-04-27 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, Maria Ballesteros-Briones, Maria Cristina Gonzalez-Aparicio, Manuela Hervas-Stubbs, Sandra Martisova, Eva Mancheño, Uxua Ricobaraza, Ana Lumbreras, Sara Smerdou, Cristian Hernandez-Alcoceba, Ruben Int J Mol Sci Article 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. MDPI 2021-04-17 /pmc/articles/PMC8073765/ /pubmed/33920699 http://dx.doi.org/10.3390/ijms22084176 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Buñuales, Maria
Ballesteros-Briones, Maria Cristina
Gonzalez-Aparicio, Manuela
Hervas-Stubbs, Sandra
Martisova, Eva
Mancheño, Uxua
Ricobaraza, Ana
Lumbreras, Sara
Smerdou, Cristian
Hernandez-Alcoceba, Ruben
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
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_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_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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073765/
https://www.ncbi.nlm.nih.gov/pubmed/33920699
http://dx.doi.org/10.3390/ijms22084176
work_keys_str_mv AT bunualesmaria adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT ballesterosbrionesmariacristina adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT gonzalezapariciomanuela adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT hervasstubbssandra adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT martisovaeva adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT manchenouxua adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT ricobarazaana adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT lumbrerassara adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT smerdoucristian adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis
AT hernandezalcocebaruben adenovirusmediatedinducibleexpressionofapdl1blockingantibodyincombinationwithmacrophagedepletionimprovessurvivalinamousemodelofperitonealcarcinomatosis