A Novel Engineering Cell Therapy Platform Mimicking the Immune Thrombocytopenia-Derived Platelets to Inhibit Cytokine Storm in Hemophagocytic Lymphohistiocytosis.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Lymphohistiocytosis, Hemophagocytic*/immunology ; Lymphohistiocytosis, Hemophagocytic*/therapy ; Cytokine Release Syndrome*/immunology ; Blood Platelets* ; Disease Models, Animal*; Animals ; Mice ; Humans ; Purpura, Thrombocytopenic, Idiopathic/immunology ; Cell- and Tissue-Based Therapy/methods ; Macrophages/immunology

Hemophagocytic lymphohistiocytosis (HLH) is a common and highly fatal hyperinflammatory syndrome characterized by the aberrant activation of macrophages. To date, there is a lack of targeted therapies for HLH. It is validated that macrophages in HLH efficiently phagocytose anti-CD41-platelets (anti-CD41-PLTs) from immune thrombocytopenia (ITP) patients in previous research. Hence, the pathological mechanisms of ITP are mimicked and anti-CD41-PLTs are utilized to load the macrophage-toxic drug VP16 to construct macrophage-targetable engineered platelets anti-CD41-PLT-VP16, which is a novel targeted therapy against HLH. Both in vitro and in vivo studies demonstrate that anti-CD41-PLT-VP16 has excellent targeting and pro-macrophage apoptotic effects. In HLH model mice, anti-CD41-PLT-VP16 prevents hemophagocytosis and inhibits the cytokine storm. Mechanistic studies reveal that anti-CD41-PLT-VP16 increases the cytotoxicity of VP16, facilitating precise intervention in macrophages. Furthermore, it operates as a strategic "besieger" in diminishing hyperinflammation syndrome, which can indirectly prevent the abnormal activation of T cells and NK cells and reduce the Ab-dependent cell-mediated cytotoxicity effect. The first platelet-based clinical trial is ongoing. The results show that after treatment with anti-CD41-PLT-VP16, HLH patients have a threefold increase in the overall response rate compared to patients receiving conventional chemotherapy. In conclusion, anti-CD41-PLT-VP16 provides a general insight into hyperinflammation syndrome and offers a novel clinical therapeutic strategy for HLH.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Biomaterials. 2021 Jan;268:120601. (PMID: 33338932)
Circulation. 2007 Jan 23;115(3):377-86. (PMID: 17224478)
Signal Transduct Target Ther. 2021 Jun 18;6(1):234. (PMID: 34140465)
Transl Oncol. 2013 Dec 01;6(6):628-37. (PMID: 24466365)
J Med Virol. 2022 Mar;94(3):869-877. (PMID: 34672376)
J Mol Med (Berl). 2014 Nov;92(11):1119-28. (PMID: 24957262)
Sci Adv. 2022 Mar 18;8(11):eabl9171. (PMID: 35302839)
World J Pediatr. 2020 Aug;16(4):333-340. (PMID: 31506890)
Science. 2011 Jul 22;333(6041):459-62. (PMID: 21778401)
Antioxid Redox Signal. 2012 Dec 15;17(12):1785-95. (PMID: 22540532)
Front Immunol. 2019 Feb 28;10:332. (PMID: 30873178)
Am J Hematol. 2022 May;97(5):623-629. (PMID: 35170082)
Front Microbiol. 2022 Dec 01;13:1046176. (PMID: 36569095)
Front Microbiol. 2023 Jul 14;14:1209870. (PMID: 37520369)
Crit Care. 2020 May 24;24(1):244. (PMID: 32448380)
Adv Sci (Weinh). 2024 Dec;11(45):e2404571. (PMID: 39258712)
Blood. 2016 Mar 31;127(13):1666-75. (PMID: 26825707)
Cell Commun Signal. 2023 Oct 10;21(1):280. (PMID: 37817178)
Nat Commun. 2021 Mar 31;12(1):1999. (PMID: 33790276)
Annu Rev Med. 2023 Jan 27;74:321-337. (PMID: 36228171)
Signal Transduct Target Ther. 2021 Sep 25;6(1):347. (PMID: 34564690)
Blood. 1991 Jul 1;78(1):51-4. (PMID: 2070059)
Immunol Rev. 2015 Mar;264(1):220-32. (PMID: 25703562)
Blood. 2002 Oct 1;100(7):2367-73. (PMID: 12239144)
Front Immunol. 2023 Jun 22;14:1210041. (PMID: 37426667)
J Hematol Oncol. 2021 Jun 4;14(1):87. (PMID: 34088334)
Exp Hematol Oncol. 2023 Jan 9;12(1):2. (PMID: 36624539)
Front Immunol. 2020 May 08;11:808. (PMID: 32457750)
Bioorg Chem. 2019 Mar;84:115-124. (PMID: 30500521)
Nat Commun. 2019 Oct 4;10(1):4520. (PMID: 31586045)
Blood. 2020 Aug 6;136(6):645-646. (PMID: 32761218)
Blood Adv. 2023 Jul 25;7(14):3561-3572. (PMID: 37042934)
Nat Chem Biol. 2023 May;19(5):641-650. (PMID: 36717711)
Blood. 2011 Oct 13;118(15):4041-52. (PMID: 21828139)
Blood. 2008 Apr 15;111(8):4293-6. (PMID: 18270327)
Lancet Haematol. 2022 Mar;9(3):e217-e227. (PMID: 35101205)
J Allergy Clin Immunol Pract. 2018 Sep - Oct;6(5):1508-1517. (PMID: 30201097)
Arch Pathol Lab Med. 2022 Apr 1;146(4):507-519. (PMID: 34347856)
Blood. 2020 Apr 16;135(16):1332-1343. (PMID: 32107531)
Crit Care Med. 2022 May 1;50(5):860-872. (PMID: 34605776)
Blood Rev. 2016 Nov;30(6):411-420. (PMID: 27238576)
Lancet Rheumatol. 2020 Jun;2(6):e358-e367. (PMID: 32373790)
J Biomed Sci. 2023 Sep 14;30(1):79. (PMID: 37704991)
Blood. 2019 Jun 6;133(23):2465-2477. (PMID: 30992265)
Front Immunol. 2021 Feb 16;12:614704. (PMID: 33664745)
Blood. 2000 Oct 1;96(7):2520-7. (PMID: 11001906)
EMBO J. 2018 Jan 4;37(1):50-62. (PMID: 29084722)
Phytomedicine. 2021 Nov;92:153729. (PMID: 34517257)
Haematologica. 2024 Feb 01;109(2):458-465. (PMID: 37470145)
Biomater Sci. 2019 Nov 1;7(11):4568-4577. (PMID: 31414106)
Blood. 2020 Mar 12;135(11):826-833. (PMID: 31914172)
J Biomed Sci. 2020 Mar 23;27(1):45. (PMID: 32200762)
Blood Adv. 2023 Dec 12;7(23):7258-7269. (PMID: 37903321)
Blood. 2017 Dec 21;130(25):2728-2738. (PMID: 28935695)
Blood. 2020 Oct 29;136(18):2065-2079. (PMID: 32556153)
Int J Biol Macromol. 2023 Jan 15;225:1182-1192. (PMID: 36423809)
Orphanet J Rare Dis. 2019 Feb 18;14(1):50. (PMID: 30777105)
Haematologica. 2023 Jan 01;108(1):234-239. (PMID: 36073517)
Curr Opin Biotechnol. 2019 Aug;58:81-91. (PMID: 30529814)
Nat Chem Biol. 2023 May;19(5):546-547. (PMID: 36717712)
Front Immunol. 2019 Feb 13;10:186. (PMID: 30814997)
Cytokine Growth Factor Rev. 2015 Jun;26(3):263-80. (PMID: 25466631)
Circ Res. 2009 Feb 27;104(4):455-65. (PMID: 19122179)

82170224 National Natural Science Foundation of China; 2023M741646 China Postdoctoral Science Foundation; 2023-LCYJ-PY-33 Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University

Keywords: cytokine storm; etoposide; hemophagocytic lymphohistiocytosis; living therapeutics platform; platelets

Date Created: 20240911 Date Completed: 20241204 Latest Revision: 20241207

20241209

PMC11615807

10.1002/advs.202404571

39258712