{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:35:08Z","timestamp":1790634908835,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T00:00:00Z","timestamp":1618617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto Salud Carlos III","award":["PI17\/01859"],"award-info":[{"award-number":["PI17\/01859"]}]},{"name":"Gobierno de Navarra, Departamento de Salud","award":["64\/2019"],"award-info":[{"award-number":["64\/2019"]}]},{"name":"Spanish Ministry of Economy and Competitiveness","award":["SAF2015-65157-R"],"award-info":[{"award-number":["SAF2015-65157-R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22084176","type":"journal-article","created":{"date-parts":[[2021,4,18]],"date-time":"2021-04-18T22:15:13Z","timestamp":1618784113000},"page":"4176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"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"],"prefix":"10.3390","volume":"22","author":[{"given":"Maria","family":"Bu\u00f1uales","sequence":"first","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cristina","family":"Ballesteros-Briones","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Gonzalez-Aparicio","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3391-1516","authenticated-orcid":false,"given":"Sandra","family":"Hervas-Stubbs","sequence":"additional","affiliation":[{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"},{"name":"Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain"},{"name":"CIBERehd, Instituto de Salud Carlos III, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Martisova","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uxua","family":"Manche\u00f1o","sequence":"additional","affiliation":[{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"},{"name":"Program of Immunology and Immunotherapy, Cima Universidad de Navarra, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Ricobaraza","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lumbreras","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian","family":"Smerdou","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6682-2598","authenticated-orcid":false,"given":"Ruben","family":"Hernandez-Alcoceba","sequence":"additional","affiliation":[{"name":"Program of Gene Therapy and Regulation of Gene Expression, Cima Universidad of Navarra, 31008 Pamplona, Spain"},{"name":"Instituto de Investigacion Sanitaria de Navarra (IdiSNA), 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","article-title":"Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation","volume":"192","author":"Freeman","year":"2000","journal-title":"J. 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