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

Jacob, Jacinta; Nadkarni, Suchita; Volpe, Alessia; Peng, Qi; Tung, Sim L.; Hannen, Rosalind; Mohseni, Yasmin R.; Scottà, Cristiano; Marelli‐Berg, Federica M.; Lechler, Robert I.; Smyth, Lesley A.; Fruhwirth, Gilbert O.; Lombardi, Giovanna

doi:10.1016/j.omtm.2020.12.003

Cited by 19 publications

(18 citation statements)

References 65 publications

(89 reference statements)

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“…Considering these limitations, it is therefore important to not overinterpret the 19 F signal as the number of viable cells at extended periods after adoptive transfer, particularly in highly dividing cell populations. A complementary imaging tool such as reporter genes, which are passed to daughter cells, would allow for both highly sensitive short-term imaging with 19 F PFCs and long-term cell viability imaging with a reporter gene [38,39]. We are currently exploring the usefulness of this combination of cellular imaging technologies for tracking CAR-T cells in preclinical cancer models.…”

Section: Discussionmentioning

confidence: 99%

Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI

et al. 2021

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Purpose Chimeric antigen receptor (CAR) T cell cancer immunotherapies have shown remarkable results in patients with hematological malignancies and represent the first approved genetically modified cellular therapies. However, not all blood cancer patients respond favorably, serious side effects have been reported, and the treatment of solid tumors has been a challenge. An imaging tool for visualizing the variety of CAR-T cell products in use and being explored could provide important patient-specific data on CAR-T cell location to inform on potential success or failure of treatment as well as off-target toxicities. Fluorine-19 (19F) magnetic resonance imaging (MRI) allows for the noninvasive detection of 19F perfluorocarbon (PFC) labeled cells. Our objective was to visualize PFC-labeled (PFC +) CAR-T cells in a mouse model of leukemia using clinical field strength (3 Tesla) 19F MRI and compare the cytotoxicity of PFC + versus unlabeled CAR-T cells. Procedures NSG mice (n = 17) received subcutaneous injections of CD19 + human B cell leukemia cells (NALM6) expressing firefly luciferase in their left hind flank (1 × 106). Twenty-one days later, each mouse received an intratumoral injection of 10 × 106 PFC + CD19-targeted CAR-T cells (n = 6), unlabeled CD19-targeted CAR-T cells (n = 3), PFC + untransduced T cells (n = 5), or an equivalent volume of saline (n = 3). 19F MRI was performed on mice treated with PFC + CAR-T cells days 1, 3, and 7 post-treatment. Bioluminescence imaging (BLI) was performed on all mice days − 1, 5, 10, and 14 post-treatment to monitor tumor response. Results PFC + CAR-T cells were successfully detected in tumors using 19F MRI on days 1, 3, and 7 post-injection. In vivo BLI data revealed that mice treated with PFC + or PFC − CAR-T cells had significantly lower tumor burden by day 14 compared to untreated mice and mice treated with PFC + untransduced T cells (p < 0.05). Importantly, mice treated with PFC + CAR-T cells showed equivalent cytotoxicity compared to mice receiving PFC − CAR-T cells. Conclusions Our studies demonstrate that clinical field strength 19F MRI can be used to visualize PFC + CAR-T cells for up to 7 days post–intratumoral injection. Importantly, PFC labeling did not significantly affect in vivo CAR-T cell cytotoxicity. These imaging tools may have broad applications for tracking emerging CAR-T cell therapies in preclinical models and may eventually be useful for the detection of CAR-T cells in patients where localized injection of CAR-T cells is being pursued.

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Section: Discussionmentioning

confidence: 99%

Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI

et al. 2021

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“…Other signal is due to the endogenous NIS expression: ThSG is thyroid+salivary glands; S is stomach. (C) In vivo trafficking and persistence at the skin graft of intravenously administered polyclonal Tregs by NIS/ 99m TcO 4 - SPECT-CT. 33 The sagittal image depicts a representative animal receiving 5×10 6 hNIS-GFP+Tregs 30 days prior to imaging and residing at the skin graft. (D) Transaxial sections show a representative nude mouse bearing different subcutaneously injected Jurkat cells.…”

Section: Molecular Imaging Of T Cell-based Immunotherapymentioning

confidence: 99%

“…Authors further demonstrated that Tregs successful trafficking to the skin graft is regulated by Gr-1 + neutrophils and monocytes. 33 …”

Section: Immune Cell Imaging Labeling Strategies and Modalitiesmentioning

confidence: 99%

“…Paramagnetic agents (eg, gadolinium) are positive contrast agents and increase the MRI signal. -SPECT-CT. 33 The sagittal image depicts a representative animal receiving 5×10 6 hNIS-GFP+Tregs 30 days prior to imaging and residing at the skin graft. (D) Transaxial sections show a representative nude mouse bearing different subcutaneously injected Jurkat cells.…”

Section: Immune Cell Imaging Labeling Strategies and Modalitiesmentioning

confidence: 99%

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Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients

Volpe

Adusumilli

Schöder

et al. 2022

J Immunother Cancer

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Cellular immunotherapies have emerged as a successful therapeutic approach to fight a wide range of human diseases, including cancer. However, responses are limited to few patients and tumor types. An in-depth understanding of the complexity and dynamics of cellular immunotherapeutics, including what is behind their success and failure in a patient, the role of other immune cell types and molecular biomarkers in determining a response, is now paramount. As the cellular immunotherapy arsenal expands, whole-body non-invasive molecular imaging can shed a light on their in vivo fate and contribute to the reliable assessment of treatment outcome and prediction of therapeutic response. In this review, we outline the non-invasive strategies that can be tailored toward the molecular imaging of cellular immunotherapies and immune-related components, with a focus on those that have been extensively tested preclinically and are currently under clinical development or have already entered the clinical trial phase. We also provide a critical appraisal on the current role and consolidation of molecular imaging into clinical practice.

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“…Some of these studies have now reached the clinical stage with multiple ongoing clinical trials utilizing NIS as a reporter gene (see above). In addition, NIS reporter imaging has been used to monitor the delivery and fate of adoptively transferred cells, such as MSCs (as outlined above), dendritic cells (Ahn et al 2017) and immune cells (Moroz et al 2015, Ashmore-Harris et al 2020, such as chimeric antigen receptor T cells (Emami-Shahri et al 2018, Volpe et al 2020) and regulatory T cells (Jacob et al 2020). Most cell therapy trials are still performed without data detailing the in vivo biodistribution and fate of administered therapeutic cells.…”

Section: Recognition Of Nis As An Important Imaging Reporter For Molecular Therapiesmentioning

confidence: 99%

The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment

Spitzweg

Nelson

Wagner³

et al. 2021

Endocrine-Related Cancer

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Cloning of the sodium iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past 2 decades significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery, towards promising new applications in disseminated disease, in particular, through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

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

Cited by 19 publications

References 65 publications

Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI

Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI

Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients

The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment

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