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Article Dans Une Revue Frontiers in Immunology Année : 2023

A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models

Kamel Chettab
  • Fonction : Auteur
Chantel Fitzsimmons
  • Fonction : Auteur
Alexey Novikov
  • Fonction : Auteur
Morgane Denis
  • Fonction : Auteur
Capucine Phelip
  • Fonction : Auteur
Doriane Mathé
  • Fonction : Auteur
Pierre Antoine Choffour
  • Fonction : Auteur
Sabine Beaumel
  • Fonction : Auteur
Eric Fourmaux
  • Fonction : Auteur
Patrick Norca
  • Fonction : Auteur
Anne Evesque
  • Fonction : Auteur
Emeline Perrial
  • Fonction : Auteur
Eva-Laure Matera
  • Fonction : Auteur
Martine Caroff
  • Fonction : Auteur
Jerome Kerzerho
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04112038 , version 1 (31-05-2023)

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Citer

Kamel Chettab, Chantel Fitzsimmons, Alexey Novikov, Morgane Denis, Capucine Phelip, et al.. A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models. Frontiers in Immunology, 2023, 14, ⟨10.3389/fimmu.2023.1066402⟩. ⟨hal-04112038⟩
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