Human Biodistribution and Radiation Dosimetry of <sup>18</sup>F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

Barrio, Martin; Spick, Claudio; Radu, Caius G.; Laßmann, Michael; Eberlein, Uta; Allen-Auerbach, Martin; Schiepers, Christiaan; Slavik, Roger; Czernin, Johannes; Herrmann, Ken

doi:10.2967/jnumed.116.182394

Cited by 17 publications

(12 citation statements)

References 15 publications

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“…Previous translational studies showed a direct correlation between [ 18 F]CFA accumulation and dCK expression in leukaemia cells, which could be blocked with a dCK inhibitor. In a first-in-human study, [ 18 F]CFA PET/CT showed preferential accumulation in hematopoietic bone marrow and secondary lymphoid organs [72, 73]. This tracer is currently being studied in metastatic melanoma patients undergoing TIM-3 targeted immunotherapy (NCT03409419).…”

Section: Cells Surface Markers For In Vivo Imaging Of T-cell Activationmentioning

confidence: 99%

Imaging of T-cells and their responses during anti-cancer immunotherapy

Krekorian¹,

Fruhwirth²,

Srinivas³

et al. 2019

Theranostics

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Immunotherapy has proven to be an effective approach in a growing number of cancers. Despite durable clinical responses achieved with antibodies targeting immune checkpoint molecules, many patients do not respond. The common denominator for immunotherapies that have successfully been introduced in the clinic is their potential to induce or enhance infiltration of cytotoxic T-cells into the tumour. However, in clinical research the molecules, cells and processes involved in effective responses during immunotherapy remain largely obscure. Therefore, in vivo imaging technologies that interrogate T-cell responses in patients represent a powerful tool to boost further development of immunotherapy. This review comprises a comprehensive analysis of the in vivo imaging technologies that allow the characterisation of T-cell responses induced by anti-cancer immunotherapy, with emphasis on technologies that are clinically available or have high translational potential. Throughout we discuss their respective strengths and weaknesses, providing arguments for selecting the optimal imaging options for future research and patient management.

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Section: Cells Surface Markers For In Vivo Imaging Of T-cell Activationmentioning

confidence: 99%

Imaging of T-cells and their responses during anti-cancer immunotherapy

Krekorian¹,

Fruhwirth²,

Srinivas³

et al. 2019

Theranostics

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“…The PET radiotracer 2-chloro-29-deoxy-29-18 F-fluoro-9-D-arabinofuranosyl-adenine is a substrate for dCK and resistant to deamination by cytidine deaminase (53). This radiotracer accumulates at high levels in lymphoid organs in humans but also at high levels in the healthy human liver (54), and high accumulation in the healthy liver would disfavor its use for imaging lymphocytes in the human liver. However, whether activated human CD4 and CD8 T cells could accumulate sufficient 18 F-FAC in the setting of high intracellular and peripheral cytidine deaminase activity to produce a PET image remains to be determined.…”

Section: Implications For Human Studiesmentioning

confidence: 99%

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

et al. 2018

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Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (F-FDG and F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [F-FAC]) and hepatocyte biology (F-2-deoxy-2-fluoroarabinose [F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged withF-FDG, F-FAC, andF-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with F-FDG,F-FAC, and F-DFA PET.F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Hepatic accumulation ofF-FDG and F-FAC was 173% and 61% higher, respectively, and hepatic accumulation ofF-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepaticF-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepaticF-FDG accumulation by 109% and decreased hepatic F-DFA accumulation by 20% but had no effect on hepaticF-FAC accumulation (nonsignificant 2% decrease). F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation ofF-FAC. Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.

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“…A number of new radiopharmaceuticals have been proposed and evaluated in pre-clinical and clinical studies aiming to distinguish rapidly proliferating immune cells invading the tumor or involved in any type of immune response. Several 18 F–labeled nucleoside analogs, including 1-(2′-Deoxy-2′-[ 18 F]fluoroarabinofuranosylcytosine (aka [ 18 F]FAC) [ 50 , 51 ], 2-chloro-2′-deoxy-2′-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine (aka [ 18 F]CFA) [ 52 , 53 ], and 2′-deoxy-2′-[ 18 F]fluoro-9-β-D-arabinofuranosylguanine (aka [ 18 F]AraG) [ 54 ] that are specific for key enzymes involved in T lymphocyte and other immune cell activation and proliferation, have been used for detecting location of activated T cells, monitoring transplant rejection, and graft– versus –host–disease and diagnosis and staging of auto–immune disorders. These new radiotracers can be early predictors of response and adverse reactions to immunotherapy measuring functional status of immune cells involved.…”

Section: Imaging Biomarkersmentioning

confidence: 99%

Advancing Immune and Cell-Based Therapies Through Imaging

Ponomarev

2017

Mol Imaging Biol

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Immunotherapies include various approaches, ranging from stimulating effector mechanisms to counteracting inhibitory and suppressive mechanisms, and creating a forum for discussing the most effective means of advancing these therapies through imaging is the focus of the newly formed Imaging in Cellular and Immune Therapies (ICIT) interest group within the World Molecular Imaging Society. Efforts are being made in the identification and validation of predictive biomarkers for a number of immunotherapies. Without predictive biomarkers, a considerable number of patients may receive treatments that have no chance of offering a benefit. This will reflect poorly on the field of immunotherapy and will yield false hopes in patients while at the same time contributing to significant cost to the healthcare system. This review summarizes the main strategies in cancer immune and cell-based therapies and discusses recent advances in imaging strategies aimed to improve cancer immunotherapy outcomes.

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Human Biodistribution and Radiation Dosimetry of ¹⁸F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

Cited by 17 publications

References 15 publications

Imaging of T-cells and their responses during anti-cancer immunotherapy

Imaging of T-cells and their responses during anti-cancer immunotherapy

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

Advancing Immune and Cell-Based Therapies Through Imaging

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Human Biodistribution and Radiation Dosimetry of 18F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

Cited by 17 publications

References 15 publications

Imaging of T-cells and their responses during anti-cancer immunotherapy

Imaging of T-cells and their responses during anti-cancer immunotherapy

18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis

Advancing Immune and Cell-Based Therapies Through Imaging

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Product

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About

Human Biodistribution and Radiation Dosimetry of ¹⁸F-Clofarabine, a PET Probe Targeting the Deoxyribonucleoside Salvage Pathway

¹⁸F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis