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A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models
Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective d...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200957/ https://www.ncbi.nlm.nih.gov/pubmed/37223101 http://dx.doi.org/10.3389/fimmu.2023.1066402 |
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author | Chettab, Kamel Fitzsimmons, Chantel Novikov, Alexey Denis, Morgane Phelip, Capucine Mathé, Doriane Choffour, Pierre Antoine Beaumel, Sabine Fourmaux, Eric Norca, Patrick Kryza, David Evesque, Anne Jordheim, Lars Petter Perrial, Emeline Matera, Eva-Laure Caroff, Martine Kerzerho, Jerome Dumontet, Charles |
author_facet | Chettab, Kamel Fitzsimmons, Chantel Novikov, Alexey Denis, Morgane Phelip, Capucine Mathé, Doriane Choffour, Pierre Antoine Beaumel, Sabine Fourmaux, Eric Norca, Patrick Kryza, David Evesque, Anne Jordheim, Lars Petter Perrial, Emeline Matera, Eva-Laure Caroff, Martine Kerzerho, Jerome Dumontet, Charles |
author_sort | Chettab, Kamel |
collection | PubMed |
description | Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer. |
format | Online Article Text |
id | pubmed-10200957 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-102009572023-05-23 A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models Chettab, Kamel Fitzsimmons, Chantel Novikov, Alexey Denis, Morgane Phelip, Capucine Mathé, Doriane Choffour, Pierre Antoine Beaumel, Sabine Fourmaux, Eric Norca, Patrick Kryza, David Evesque, Anne Jordheim, Lars Petter Perrial, Emeline Matera, Eva-Laure Caroff, Martine Kerzerho, Jerome Dumontet, Charles Front Immunol Immunology Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer. Frontiers Media S.A. 2023-05-08 /pmc/articles/PMC10200957/ /pubmed/37223101 http://dx.doi.org/10.3389/fimmu.2023.1066402 Text en Copyright © 2023 Chettab, Fitzsimmons, Novikov, Denis, Phelip, Mathé, Choffour, Beaumel, Fourmaux, Norca, Kryza, Evesque, Jordheim, Perrial, Matera, Caroff, Kerzerho and Dumontet https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Chettab, Kamel Fitzsimmons, Chantel Novikov, Alexey Denis, Morgane Phelip, Capucine Mathé, Doriane Choffour, Pierre Antoine Beaumel, Sabine Fourmaux, Eric Norca, Patrick Kryza, David Evesque, Anne Jordheim, Lars Petter Perrial, Emeline Matera, Eva-Laure Caroff, Martine Kerzerho, Jerome Dumontet, Charles A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title_full | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title_fullStr | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title_full_unstemmed | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title_short | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
title_sort | systemically administered detoxified tlr4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10200957/ https://www.ncbi.nlm.nih.gov/pubmed/37223101 http://dx.doi.org/10.3389/fimmu.2023.1066402 |
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