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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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.
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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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