Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90

Allogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (...

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Autores principales:	Tanmoy Saha, Amanda A. van Vliet, Chunxiao Cui, Jorge Jimenez Macias, Arpita Kulkarni, Luu Nhat Pham, Sean Lawler, Jan Spanholtz, Anna-Maria Georgoudaki, Adil Doganay Duru, Aaron Goldman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	cell therapy glioblastoma multiforme nanotechnology natural killer cells (NK cells) allogeneic natural killer cells Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e47ed6b00c7f48eaa54b2fa0f80f11a6
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spelling	oai:doaj.org-article:e47ed6b00c7f48eaa54b2fa0f80f11a62021-12-01T23:45:10ZBoosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 902296-889X10.3389/fmolb.2021.754443https://doaj.org/article/e47ed6b00c7f48eaa54b2fa0f80f11a62021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.754443/fullhttps://doaj.org/toc/2296-889XAllogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (MICA/B) and ULBPs. Here, we describe the use of a blood–brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002). First, we identify Hsp90 mRNA transcription and gain of function as significantly upregulated in GBM compared to other central nervous system tumors. Through a rational chemical design, we optimize a radicicol supramolecular prodrug containing cationic excipients, SCI-101, which displays >2-fold increase in relative BBB penetration compared to less cationic formulations in organoids, in vitro. Using 2D and 3D biological models, we confirm SCI-101 sustains GBM cytotoxicity 72 h after drug removal and induces cell surface MICA/B protein and ULBP mRNA up to 200% in residual tumor cells compared to the naked drug alone without augmenting the shedding of MICA/B, in vitro. Finally, we generate and test the sequential administration of SCI-101 with a clinical aNK cell therapy, GTA002, differentiated and expanded from healthy umbilical cord blood CD34+ hematopoietic stem cells. Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101–treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM.Tanmoy SahaTanmoy SahaAmanda A. van VlietChunxiao CuiJorge Jimenez MaciasArpita KulkarniArpita KulkarniLuu Nhat PhamSean LawlerJan SpanholtzAnna-Maria GeorgoudakiAdil Doganay DuruAaron GoldmanAaron GoldmanAaron GoldmanAaron GoldmanFrontiers Media S.A.articlecell therapyglioblastoma multiformenanotechnologynatural killer cells (NK cells)allogeneic natural killer cellsBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cell therapy glioblastoma multiforme nanotechnology natural killer cells (NK cells) allogeneic natural killer cells Biology (General) QH301-705.5
spellingShingle	cell therapy glioblastoma multiforme nanotechnology natural killer cells (NK cells) allogeneic natural killer cells Biology (General) QH301-705.5 Tanmoy Saha Tanmoy Saha Amanda A. van Vliet Chunxiao Cui Jorge Jimenez Macias Arpita Kulkarni Arpita Kulkarni Luu Nhat Pham Sean Lawler Jan Spanholtz Anna-Maria Georgoudaki Adil Doganay Duru Aaron Goldman Aaron Goldman Aaron Goldman Aaron Goldman Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
description	Allogeneic natural killer (aNK) cell adoptive therapy has the potential to dramatically impact clinical outcomes of glioblastoma multiforme (GBM). However, in order to exert therapeutic activity, NK cells require tumor expression of ligands for activating receptors, such as MHC Class I peptide A/B (MICA/B) and ULBPs. Here, we describe the use of a blood–brain barrier (BBB) permissive supramolecular cationic drug vehicle comprising an inhibitor of the chaperone heat shock protein 90 (Hsp90), which sustains a cytotoxic effect on GBM cells, boosts the expression of MICA/B and ULBPs on the residual population, and augments the activity of clinical-grade aNK cells (GTA002). First, we identify Hsp90 mRNA transcription and gain of function as significantly upregulated in GBM compared to other central nervous system tumors. Through a rational chemical design, we optimize a radicicol supramolecular prodrug containing cationic excipients, SCI-101, which displays >2-fold increase in relative BBB penetration compared to less cationic formulations in organoids, in vitro. Using 2D and 3D biological models, we confirm SCI-101 sustains GBM cytotoxicity 72 h after drug removal and induces cell surface MICA/B protein and ULBP mRNA up to 200% in residual tumor cells compared to the naked drug alone without augmenting the shedding of MICA/B, in vitro. Finally, we generate and test the sequential administration of SCI-101 with a clinical aNK cell therapy, GTA002, differentiated and expanded from healthy umbilical cord blood CD34+ hematopoietic stem cells. Using a longitudinal in vitro model, we demonstrate >350% relative cell killing is achieved in SCI-101–treated cell lines compared to vehicle controls. In summary, these data provide a first-of-its-kind BBB-penetrating, long-acting inhibitor of Hsp90 with monotherapy efficacy, which improves response to aNK cells and thus may rapidly alter the treatment paradigm for patients with GBM.
format	article
author	Tanmoy Saha Tanmoy Saha Amanda A. van Vliet Chunxiao Cui Jorge Jimenez Macias Arpita Kulkarni Arpita Kulkarni Luu Nhat Pham Sean Lawler Jan Spanholtz Anna-Maria Georgoudaki Adil Doganay Duru Aaron Goldman Aaron Goldman Aaron Goldman Aaron Goldman
author_facet	Tanmoy Saha Tanmoy Saha Amanda A. van Vliet Chunxiao Cui Jorge Jimenez Macias Arpita Kulkarni Arpita Kulkarni Luu Nhat Pham Sean Lawler Jan Spanholtz Anna-Maria Georgoudaki Adil Doganay Duru Aaron Goldman Aaron Goldman Aaron Goldman Aaron Goldman
author_sort	Tanmoy Saha
title	Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
title_short	Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
title_full	Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
title_fullStr	Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
title_full_unstemmed	Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90
title_sort	boosting natural killer cell therapies in glioblastoma multiforme using supramolecular cationic inhibitors of heat shock protein 90
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e47ed6b00c7f48eaa54b2fa0f80f11a6
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Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90

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