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.) |
| References: | Acta Pharmacol Sin. 2019 Sep;40(9):1168-1183. (PMID: 30858476) Sci Rep. 2013 Oct 16;3:2960. (PMID: 24129891) J Biol Chem. 2002 Dec 6;277(49):47834-43. (PMID: 12324469) J Exp Med. 1978 Dec 1;148(6):1560-9. (PMID: 309922) Lancet. 2007 Jun 30;369(9580):2161-2170. (PMID: 17602732) Cancer Res. 1991 May 15;51(10):2524-30. (PMID: 2021932) J Leukoc Biol. 2010 Dec;88(6):1227-39. (PMID: 20826611) Methods Mol Biol. 2011;739:135-46. (PMID: 21567324) Infect Immun. 1989 Mar;57(3):791-7. (PMID: 2537258) Infect Immun. 1980 Mar;27(3):739-45. (PMID: 6247278) Biochim Biophys Acta. 2016 Apr;1863(4):660-72. (PMID: 26804480) Cells. 2020 Jun 24;9(6):. (PMID: 32599709) Int J Mol Sci. 2021 Jun 29;22(13):. (PMID: 34209703) Oncotarget. 2017 Jul 08;8(39):66656-66667. (PMID: 29029545) Curr Med Chem. 2020;27(17):2887-2901. (PMID: 30362416) Clin Cancer Res. 2019 Feb 15;25(4):1185-1195. (PMID: 30093453) Clin Ther. 2020 Aug;42(8):1519-1534.e33. (PMID: 32739049) Expert Opin Biol Ther. 2019 Jul;19(7):707-720. (PMID: 31081696) Infect Immun. 2000 Nov;68(11):6202-8. (PMID: 11035726) J Cancer Res Clin Oncol. 2014 Nov;140(11):1815-23. (PMID: 24927808) Expert Rev Vaccines. 2007 Apr;6(2):133-40. (PMID: 17408363) Curr Biol. 2017 Jul 24;27(14):2065-2077.e6. (PMID: 28669759) PLoS One. 2013 May 27;8(5):e63967. (PMID: 23724011) Cancer Immunol Immunother. 1996 May;42(4):255-61. (PMID: 8665574) Nanoscale Horiz. 2021 Feb 1;6(2):78-94. (PMID: 33400747) J Clin Invest. 2000 Feb;105(4):497-504. (PMID: 10683379) Cancer Cell Int. 2021 Jul 21;21(1):389. (PMID: 34289846) Cancer Res. 1981 Jul;41(7):2654-7. (PMID: 7018667) Nature. 2019 Oct;574(7776):45-56. (PMID: 31578484) Cells. 2021 Nov 16;10(11):. (PMID: 34831416) J Exp Med. 1997 Jun 16;185(12):2089-94. (PMID: 9182680) Int J Immunopathol Pharmacol. 2013 Oct-Dec;26(4):861-9. (PMID: 24355221) Front Immunol. 2020 Jul 10;11:1210. (PMID: 32765484) Science. 2007 Jun 15;316(5831):1628-32. (PMID: 17569868) Ann Oncol. 2001 Apr;12(4):433-4. (PMID: 11398872) J Cell Biochem. 2019 Mar;120(3):2756-2765. (PMID: 30270458) Neurosurgery. 2001 Mar;48(3):607-14; discussion 614-5. (PMID: 11270552) Leuk Lymphoma. 2022 Apr;63(4):821-833. (PMID: 34865586) Front Immunol. 2014 Jul 10;5:316. (PMID: 25071777) J Pharmacol Exp Ther. 2013 Dec;347(3):599-606. (PMID: 24042160) Proc Natl Acad Sci U S A. 2017 May 16;114(20):E3954-E3963. (PMID: 28461481) MAbs. 2015;7(1):192-8. (PMID: 25523586) Infect Immun. 1970 May;1(5):440-5. (PMID: 16557755) Mol Pharm. 2018 Nov 5;15(11):4777-4800. (PMID: 30226786) Cancer Res. 2019 Jan 1;79(1):159-170. (PMID: 30224373) J Vet Intern Med. 2020 Mar;34(2):653-658. (PMID: 31970837) PLoS One. 2013 Jul 17;8(7):e68671. (PMID: 23874715) PLoS One. 2013 Oct 18;8(10):e76338. (PMID: 24204616) Drug Resist Updat. 2016 Nov;29:90-106. (PMID: 27912846) J Chemother. 2004 Nov;16 Suppl 4:94-7. (PMID: 15688621) J Bacteriol. 1994 Aug;176(16):5156-9. (PMID: 8051033) J Immunol. 2008 Aug 1;181(3):1849-58. (PMID: 18641322) Cancer Res. 2016 Feb 1;76(3):513-6. (PMID: 26772756) J Biol Chem. 2018 Jun 29;293(26):10186-10201. (PMID: 29760187) Sci Rep. 2020 Jul 23;10(1):12273. (PMID: 32703960) |
| 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 |
Full Text Finder | تدمد: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2023.1066402 |