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Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo

Antibody-mediated blockade of CTLA4 has been shown to be effective in treating a select group of patients with late-stage melanoma. The precise mechanism underlying the clinical activity of CTLA4 immunotherapy is poorly understood, although recent experimental findings indicate that antibody-mediate...

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Autores principales: Sandin, Linda C, Eriksson, Fredrik, Ellmark, Peter, Loskog, Angelica SI, Tötterman, Thomas H, Mangsbo, Sara M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Landes Bioscience 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962508/
https://www.ncbi.nlm.nih.gov/pubmed/24701377
http://dx.doi.org/10.4161/onci.27614
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author Sandin, Linda C
Eriksson, Fredrik
Ellmark, Peter
Loskog, Angelica SI
Tötterman, Thomas H
Mangsbo, Sara M
author_facet Sandin, Linda C
Eriksson, Fredrik
Ellmark, Peter
Loskog, Angelica SI
Tötterman, Thomas H
Mangsbo, Sara M
author_sort Sandin, Linda C
collection PubMed
description Antibody-mediated blockade of CTLA4 has been shown to be effective in treating a select group of patients with late-stage melanoma. The precise mechanism underlying the clinical activity of CTLA4 immunotherapy is poorly understood, although recent experimental findings indicate that antibody-mediated depletion of regulatory T cells (Tregs) in the tumor microenvironment plays a key role in efficacious antitumor responses. In the current study, we used an experimental model of pancreatic adenocarcinoma to compare the antitumor efficacy of peritumoral low-dose anti-CTLA4 monoclonal antibody (mAb) administration to that of a commonly utilized systemic high-dose anti-CTLA4 regimen. We selected pancreatic adenocarcinoma as it presents a particular challenge to clinicians due to its aggressive behavior, metastatic spread and limited treatment options. Furthermore, Fc gamma receptor (FcγR)-dense myeloid cells commonly infiltrate pancreatic tumors, such that these tumor types exhibit increased susceptibility to CTLA4 antibody-targeted Treg depletion via antibody-dependent cell-mediated cytotoxicity (ADCC). Locally administered anti-CTLA4 mAb effectively reduced tumor growth at a low dose and no additional anti-tumor effects were apparent when increasing the dose or number of injections. No significant difference in overall survival was seen when comparing locally administered low-dose with standard systemic high-dose CTLA4 blockade therapy, and both delivery routes led to increased tumor-infiltrating effector T cells and reduced Treg cells. As opposed to low-dose peritumoral treatment, high-dose systemic therapy stimulated the accumulation of Tregs in secondary lymphoid organs, an effect that could potentially counteract the antitumor immunotherapeutic benefit of CTLA4 blockade. Our study confirms previous findings that local administration of low-dose anti-CTLA4 antibody generates sustained antitumor effects and provides rationale to devise ultrasound-guided intratumoral anti-CTLA4 antibody injection regimens to treat patients with pancreatic adenocarcinoma and other types of solid tumors. In support, clinical relevancy could include reduced immune-related adverse events by limiting systemic antibody spread to immune cell-dense organs.
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spelling pubmed-39625082014-04-03 Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo Sandin, Linda C Eriksson, Fredrik Ellmark, Peter Loskog, Angelica SI Tötterman, Thomas H Mangsbo, Sara M Oncoimmunology Original Research Antibody-mediated blockade of CTLA4 has been shown to be effective in treating a select group of patients with late-stage melanoma. The precise mechanism underlying the clinical activity of CTLA4 immunotherapy is poorly understood, although recent experimental findings indicate that antibody-mediated depletion of regulatory T cells (Tregs) in the tumor microenvironment plays a key role in efficacious antitumor responses. In the current study, we used an experimental model of pancreatic adenocarcinoma to compare the antitumor efficacy of peritumoral low-dose anti-CTLA4 monoclonal antibody (mAb) administration to that of a commonly utilized systemic high-dose anti-CTLA4 regimen. We selected pancreatic adenocarcinoma as it presents a particular challenge to clinicians due to its aggressive behavior, metastatic spread and limited treatment options. Furthermore, Fc gamma receptor (FcγR)-dense myeloid cells commonly infiltrate pancreatic tumors, such that these tumor types exhibit increased susceptibility to CTLA4 antibody-targeted Treg depletion via antibody-dependent cell-mediated cytotoxicity (ADCC). Locally administered anti-CTLA4 mAb effectively reduced tumor growth at a low dose and no additional anti-tumor effects were apparent when increasing the dose or number of injections. No significant difference in overall survival was seen when comparing locally administered low-dose with standard systemic high-dose CTLA4 blockade therapy, and both delivery routes led to increased tumor-infiltrating effector T cells and reduced Treg cells. As opposed to low-dose peritumoral treatment, high-dose systemic therapy stimulated the accumulation of Tregs in secondary lymphoid organs, an effect that could potentially counteract the antitumor immunotherapeutic benefit of CTLA4 blockade. Our study confirms previous findings that local administration of low-dose anti-CTLA4 antibody generates sustained antitumor effects and provides rationale to devise ultrasound-guided intratumoral anti-CTLA4 antibody injection regimens to treat patients with pancreatic adenocarcinoma and other types of solid tumors. In support, clinical relevancy could include reduced immune-related adverse events by limiting systemic antibody spread to immune cell-dense organs. Landes Bioscience 2014-01-16 /pmc/articles/PMC3962508/ /pubmed/24701377 http://dx.doi.org/10.4161/onci.27614 Text en Copyright © 2014 Landes Bioscience http://creativecommons.org/licenses/by-nc/3.0/ This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Original Research
Sandin, Linda C
Eriksson, Fredrik
Ellmark, Peter
Loskog, Angelica SI
Tötterman, Thomas H
Mangsbo, Sara M
Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title_full Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title_fullStr Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title_full_unstemmed Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title_short Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
title_sort local ctla4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962508/
https://www.ncbi.nlm.nih.gov/pubmed/24701377
http://dx.doi.org/10.4161/onci.27614
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