دورية أكاديمية
A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models.
العنوان: | A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models. |
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المؤلفون: | Chettab K; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France.; Hospices Civils de Lyon, Lyon, France., Fitzsimmons C; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Novikov A; HEPHAISTOS-Pharma, Université Paris-Saclay, Orsay, France., Denis M; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France.; Antinéo, Lyon, France., Phelip C; HEPHAISTOS-Pharma, Université Paris-Saclay, Orsay, France., Mathé D; Antinéo, Lyon, France., Choffour PA; Antinéo, Lyon, France., Beaumel S; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Fourmaux E; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Norca P; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Kryza D; Hospices Civils de Lyon, Lyon, France., Evesque A; Antinéo, Lyon, France., Jordheim LP; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Perrial E; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Matera EL; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France., Caroff M; HEPHAISTOS-Pharma, Université Paris-Saclay, Orsay, France., Kerzerho J; HEPHAISTOS-Pharma, Université Paris-Saclay, Orsay, France., Dumontet C; INSERM U1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, Université de Lyon, Lyon, France.; Hospices Civils de Lyon, Lyon, France. |
المصدر: | Frontiers in immunology [Front Immunol] 2023 May 08; Vol. 14, pp. 1066402. Date of Electronic Publication: 2023 May 08 (Print Publication: 2023). |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
مواضيع طبية MeSH: | Adjuvants, Immunologic* , Lipopolysaccharides* , Toll-Like Receptor 4*/agonists, Animals ; Dogs ; Humans ; Mice ; Cytokines ; Liposomes |
مستخلص: | 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. Competing Interests: KC, AN, JK, and MC are shareholders in HEPHAISTOS-Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Chettab, Fitzsimmons, Novikov, Denis, Phelip, Mathé, Choffour, Beaumel, Fourmaux, Norca, Kryza, Evesque, Jordheim, Perrial, Matera, Caroff, Kerzerho and Dumontet.) |
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فهرسة مساهمة: | Keywords: adjuvant effect; in vivo antitumor activity; lipopolysaccharides; liposomal formulation; modified TLR4 agonist; tolerance |
المشرفين على المادة: | 0 (Adjuvants, Immunologic) 0 (Cytokines) 0 (Lipopolysaccharides) 0 (Liposomes) 0 (TLR4 protein, human) 0 (Tlr4 protein, mouse) 0 (Toll-Like Receptor 4) |
تواريخ الأحداث: | Date Created: 20230524 Date Completed: 20230612 Latest Revision: 20230612 |
رمز التحديث: | 20230613 |
مُعرف محوري في PubMed: | PMC10200957 |
DOI: | 10.3389/fimmu.2023.1066402 |
PMID: | 37223101 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1664-3224 |
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DOI: | 10.3389/fimmu.2023.1066402 |