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The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3

SIMPLE SUMMARY: Malignant pleural mesothelioma is an aggressive cancer most commonly associated with asbestos exposure. Its prognosis is very poor, and the current treatments have only a limited impact on survival. Therefore, there is an urgent need to develop new treatment strategies. We investigat...

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Autores principales: Marcq, Elly, Van Audenaerde, Jonas R. M., De Waele, Jorrit, Merlin, Céline, Pauwels, Patrick, van Meerbeeck, Jan P., Fisher, Scott A., Smits, Evelien L. J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838786/
https://www.ncbi.nlm.nih.gov/pubmed/33466653
http://dx.doi.org/10.3390/cancers13020282
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author Marcq, Elly
Van Audenaerde, Jonas R. M.
De Waele, Jorrit
Merlin, Céline
Pauwels, Patrick
van Meerbeeck, Jan P.
Fisher, Scott A.
Smits, Evelien L. J.
author_facet Marcq, Elly
Van Audenaerde, Jonas R. M.
De Waele, Jorrit
Merlin, Céline
Pauwels, Patrick
van Meerbeeck, Jan P.
Fisher, Scott A.
Smits, Evelien L. J.
author_sort Marcq, Elly
collection PubMed
description SIMPLE SUMMARY: Malignant pleural mesothelioma is an aggressive cancer most commonly associated with asbestos exposure. Its prognosis is very poor, and the current treatments have only a limited impact on survival. Therefore, there is an urgent need to develop new treatment strategies. We investigated combinations of different immune checkpoint blocking antibodies that have already shown promising results in several cancer types. We suggested that the effect of a combination treatment might even be better than one, single therapy. Based on our in vitro results about the secretion of several immune related molecules we selected promising treatments for further investigation in a mesothelioma mouse model. We found that monotherapy with an immune checkpoint blocking antibody against programmed death-1 (PD-1), and its combination with another blocking antibody against lymphocyte activation gene-3 (LAG-3), resulted in delayed tumor growth and survival benefit in our mice. Further research is warranted to optimize the treatment schedule of the combination therapy. ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.
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spelling pubmed-78387862021-01-28 The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3 Marcq, Elly Van Audenaerde, Jonas R. M. De Waele, Jorrit Merlin, Céline Pauwels, Patrick van Meerbeeck, Jan P. Fisher, Scott A. Smits, Evelien L. J. Cancers (Basel) Article SIMPLE SUMMARY: Malignant pleural mesothelioma is an aggressive cancer most commonly associated with asbestos exposure. Its prognosis is very poor, and the current treatments have only a limited impact on survival. Therefore, there is an urgent need to develop new treatment strategies. We investigated combinations of different immune checkpoint blocking antibodies that have already shown promising results in several cancer types. We suggested that the effect of a combination treatment might even be better than one, single therapy. Based on our in vitro results about the secretion of several immune related molecules we selected promising treatments for further investigation in a mesothelioma mouse model. We found that monotherapy with an immune checkpoint blocking antibody against programmed death-1 (PD-1), and its combination with another blocking antibody against lymphocyte activation gene-3 (LAG-3), resulted in delayed tumor growth and survival benefit in our mice. Further research is warranted to optimize the treatment schedule of the combination therapy. ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9–12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit. MDPI 2021-01-14 /pmc/articles/PMC7838786/ /pubmed/33466653 http://dx.doi.org/10.3390/cancers13020282 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Marcq, Elly
Van Audenaerde, Jonas R. M.
De Waele, Jorrit
Merlin, Céline
Pauwels, Patrick
van Meerbeeck, Jan P.
Fisher, Scott A.
Smits, Evelien L. J.
The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title_full The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title_fullStr The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title_full_unstemmed The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title_short The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3
title_sort search for an interesting partner to combine with pd-l1 blockade in mesothelioma: focus on tim-3 and lag-3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838786/
https://www.ncbi.nlm.nih.gov/pubmed/33466653
http://dx.doi.org/10.3390/cancers13020282
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