Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem Cells

Ashmore-Harris, Candice; Iafrate, Madeleine; Saleem, Adeel; Fruhwirth, Gilbert O.

doi:10.1016/j.ymthe.2020.03.016

Cited by 52 publications

(62 citation statements)

References 228 publications

(164 reference statements)

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“…This may not only allow to assess an individual efficacy profile, but also help to reduce, or even prevent, side effects. Specifically, iron or gadolinium-(NP) labelled stem cells can be detected by MRI [ 48 , 49 ], or, more recently, advanced approaches were developed using reporter gene imaging that could combine graft tracking with its functional assessment such as viability or therapeutic capacities [50] .…”

Section: Discussionmentioning

confidence: 99%

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Schäfer

Schwab

Siegel³

et al. 2020

EBioMedicine

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Background Limited knowledge of stem cell therapies` mechanisms of action hampers their sustainable implementation into the clinic. Specifically, the interactions of transplanted stem cells with the host vasculature and its implications for their therapeutic efficacy are not elucidated. We tested whether adhesion receptors and chemokine receptors on stem cells can be functionally modulated, and consequently if such modulation may substantially affect therapeutically relevant stem cell interactions with the host endothelium. Methods We investigated the effects of cationic molecule polyethylenimine (PEI) treatment with or without nanoparticles on the functions of adhesion receptors and chemokine receptors of human bone marrow-derived Mesenchymal Stem Cells (MSC). Analyses included MSC functions in vitro, as well as homing and therapeutic efficacy in rodent models of central nervous system´s pathologies in vivo. Findings PEI treatment did not affect viability, immunomodulation or differentiation potential of MSC, but increased the CCR4 expression and functionally blocked their adhesion receptors, thus decreasing their adhesion capacity in vitro. Intravenously applied in a rat model of brain injury, the homing rate of PEI-MSC in the brain was highly increased with decreased numbers of adherent PEI-MSC in the lung vasculature. Moreover, in comparison to untreated MSC, PEI-MSC featured increased tumour directed migration in a mouse glioblastoma model, and superior therapeutic efficacy in a murine model of stroke. Interpretation Balanced stem cell adhesion and migration in different parts of the vasculature and tissues together with the local microenvironment impacts their therapeutic efficacy. Funding Robert Bosch Stiftung, IZEPHA grant, EU grant 7 FP Health

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Section: Discussionmentioning

confidence: 99%

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Schäfer

Schwab

Siegel³

et al. 2020

EBioMedicine

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“…Cell labeling approaches can be direct or indirect, with each approach offering distinct advantages and disadvantages. 16 We showed previously that direct radiolabeling of murine CD4 + T cells, with 99 m Tc-hexamethylpropyleneamine oxime, did not affect cell viability, but the radiolabeled cells could only be tracked for up to 24 h because of the short radioisotope half-life of 99 m Tc (6 h). 17 This enabled assessment of Treg biodistribution within a day after administration but precluded the desired long-term tracking of Tregs, which would require longer half-life radioisotopes.…”

Section: Introductionmentioning

confidence: 95%

Spatiotemporal in vivo tracking of polyclonal human regulatory T cells (Tregs) reveals a role for innate immune cells in Treg transplant recruitment

Jacob

Nadkarni

Volpe

et al. 2021

Molecular Therapy - Methods & Clinical Development

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“…The field of in vivo cell tracking has re-gained new momentum through the development of adoptive cell therapies. The various cell tracking methodologies including a variety of experimental design considerations and caveats have recently been comprehensively reviewed (98), also in the context of tracking T cell therapies (99). Fundamentally, cells require labeling to visualize them in vivo using technologies with exquisite sensitivities.…”

Section: Reporters For Spatiotemporal In Vivo Trackingmentioning

confidence: 99%

“…The alternative is "indirect cell labeling, " whereby a genetically encoded reporter is ectopically introduced into the cells mostly by viral transduction to ensure genomic integration and thus stable long-term expression; transposon and gene editing represent alternative methodologies (106,107). Reporter genes have critical advantages over direct labeling for cell tracking (99,108). First, the observation period is independent of the contrast agent, for example, not affected by the half-life of a radioisotope.…”

Section: Reporters For Spatiotemporal In Vivo Trackingmentioning

confidence: 99%

“…As foreign reporters can elicit an immune response and result in immune destruction of the administered therapeutic cells, a host-compatible reporter is preferable in this context. Host reporters are from the same species but endogenously expressed in only a very limited number of host tissues, and ideally at low levels to ensure favorable contrast ( 99 ). The most promising host reporters available for the purpose of Treg tracking in skin transplant models are the human sodium iodide symporter (NIS) ( 111 ) and the human prostate-specific membrane antigen (PSMA) ( 112 ), as neither of them is expressed in human or mouse dermis or epidermis.…”

Section: Engineering Beyond the Carmentioning

confidence: 99%

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The Future of Regulatory T Cell Therapy: Promises and Challenges of Implementing CAR Technology

et al. 2020

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Cell therapy with polyclonal regulatory T cells (Tregs) has been translated into the clinic and is currently being tested in transplant recipients and patients suffering from autoimmune diseases. Moreover, building on animal models, it has been widely reported that antigen-specific Tregs are functionally superior to polyclonal Tregs. Among various options to confer target specificity to Tregs, genetic engineering is a particularly timely one as has been demonstrated in the treatment of hematological malignancies where it is in routine clinical use. Genetic engineering can be exploited to express chimeric antigen receptors (CAR) in Tregs, and this has been successfully demonstrated to be robust in preclinical studies across various animal disease models. However, there are several caveats and a number of strategies should be considered to further improve on targeting, efficacy and to understand the in vivo distribution and fate of CAR-Tregs. Here, we review the differing approaches to confer antigen specificity to Tregs with emphasis on CAR-Tregs. This includes an overview and discussion of the various approaches to improve CAR-Treg specificity and therapeutic efficacy as well as addressing potential safety concerns. We also discuss different imaging approaches to understand the in vivo biodistribution of administered Tregs. Preclinical research as well as suitability of methodologies for clinical translation are discussed.

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Non-invasive Reporter Gene Imaging of Cell Therapies, including T Cells and Stem Cells

Cited by 52 publications

References 228 publications

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Modulating endothelial adhesion and migration impacts stem cell therapies efficacy

Spatiotemporal in vivo tracking of polyclonal human regulatory T cells (Tregs) reveals a role for innate immune cells in Treg transplant recruitment

The Future of Regulatory T Cell Therapy: Promises and Challenges of Implementing CAR Technology

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