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In vivo nanoparticle-based T cell imaging can predict therapy response towards adoptive T cell therapy in experimental glioma

Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) including chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cell therapy targeting glioma-associated antigens are an eme...

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Main Authors: Hunger, Jessica (Author) , Schregel, Katharina (Author) , Boztepe, Berin (Author) , Agardy, Dennis (Author) , Turco, Verena (Author) , Karimian-Jazi, Kianush (Author) , Weidenfeld, Ina (Author) , Streibel, Yannik (Author) , Fischer, Manuel (Author) , Sturm, Volker Jörg Friedrich (Author) , Santarella-Mellwig, Rachel (Author) , Kilian, Michael (Author) , Jähne, Kristine (Author) , Sahm, Katharina (Author) , Wick, Wolfgang (Author) , Bunse, Lukas (Author) , Heiland, Sabine (Author) , Bunse, Theresa (Author) , Bendszus, Martin (Author) , Platten, Michael (Author) , Breckwoldt, Michael O. (Author)
Format: Article (Journal)
Language:English
Published: 2023.09.25
In: Theranostics
Year: 2023, Volume: 13, Issue: 15, Pages: 5170-5182
ISSN:1838-7640
DOI:10.7150/thno.87248
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.7150/thno.87248
Verlag, lizenzpflichtig, Volltext: https://www.thno.org/v13p5170.htm
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Author Notes:Jessica Hunger, Katharina Schregel, Berin Boztepe, Dennis Alexander Agardy, Verena Turco, Kianush Karimian-Jazi, Ina Weidenfeld, Yannik Streibel, Manuel Fischer, Volker Sturm, Rachel Santarella-Mellwig, Michael Kilian, Kristine Jähne, Katharina Sahm, Wolfgang Wick, Lukas Bunse, Sabine Heiland, Theresa Bunse, Martin Bendszus, Michael Platten and Michael O. Breckwoldt
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Summary:Rationale: Intrinsic brain tumors, such as gliomas are largely resistant to immunotherapies including immune checkpoint blockade. Adoptive cell therapies (ACT) including chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cell therapy targeting glioma-associated antigens are an emerging field in glioma immunotherapy. However, imaging techniques for non-invasive monitoring of adoptively transferred T cells homing to the glioma microenvironment are currently lacking. Methods: Ultrasmall iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Here, we develop a protocol for efficient ex vivo labeling of murine and human TCR-transgenic and CAR T cells with iron oxide NPs. We assess labeling efficiency and T cell functionality by flow cytometry and transmission electron microscopy (TEM). NP labeled T cells are visualized by MRI at 9.4 T in vivo after adoptive T cell transfer and correlated with 3D models of cleared brains obtained by light sheet microscopy (LSM). Results: NP are incorporated into T cells in subcellular cytoplasmic vesicles with high labeling efficiency without interfering with T cell viability, proliferation and effector function as assessed by cytokine secretion and antigen-specific killing assays in vitro. We further demonstrate that adoptively transferred T cells can be longitudinally monitored intratumorally by high field MRI at 9.4 Tesla in a murine glioma model with high sensitivity. We find that T cell influx and homogenous spatial distribution of T cells within the TME as assessed by T2* imaging predicts tumor response to ACT whereas incomplete T cell coverage results in treatment resistance. Conclusion: This study showcases a rational for monitoring adoptive T cell therapies non-invasively by iron oxide NP in gliomas to track intratumoral T cell influx and ultimately predict treatment outcome.
Item Description:Gesehen am 20.06.2024
Physical Description:Online Resource
ISSN:1838-7640
DOI:10.7150/thno.87248

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