Noninvasive monitoring of cancer therapy induced activated T cells using [18F]FB-IL-2 PET imaging.
Ontology highlight
ABSTRACT:
SUBMITTER: Hartimath SV
PROVIDER: S-EPMC5283633 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
Noninvasive monitoring of cancer therapy induced activated T cells using [<sup>18</sup>F]FB-IL-2 PET imaging.
Hartimath S V SV Draghiciu O O van de Wall S S Manuelli V V Dierckx R A J O RA Nijman H W HW Daemen T T de Vries E F J EF
Oncoimmunology 20161118 1
Cancer immunotherapy urgently calls for methods to monitor immune responses at the site of the cancer. Since activated T lymphocytes may serve as a hallmark for anticancer responses, we targeted these cells using the radiotracer N-(4-[<sup>18</sup>F]fluorobenzoyl)-interleukin-2 ([<sup>18</sup>F]FB-IL-2) for positron emission tomography (PET) imaging. Thus, we noninvasively monitored the effects of local tumor irradiation and/or immunization on tumor-infiltrating and systemic activated lymphocyte ...[more]
Similar Datasets
Project description:BackgroundReprogrammed cellular metabolism is a cancer hallmark. In addition to increased glycolysis, the oxidation of acetate in the citric acid cycle is another common metabolic phenotype. We have recently developed a novel fluorine-18-labelled trimethylacetate-based radiotracer, [18F]fluoro-pivalic acid ([18F]FPIA), for imaging the transcellular flux of short-chain fatty acids, and investigated whether this radiotracer can be used for the detection of glioma growth.MethodsWe evaluated the potential of [18F]FPIA PET to monitor tumor growth in orthotopic patient-derived (HSJD-GBM-001) and cell line-derived (U87, LN229) glioma xenografts, and also included [18F]FDG PET for comparison. We assessed proliferation (Ki-67) and the expression of lipid metabolism and transport proteins (CPT1, SLC22A2, SLC22A5, SLC25A20) by immunohistochemistry, along with etomoxir treatment to provide insights into [18F]FPIA uptake.ResultsLongitudinal PET imaging showed gradual increase in [18F]FPIA uptake in orthotopic glioma models with disease progression (p < 0.0001), and high tumor-to-brain contrast compared to [18F]FDG (p < 0.0001). [18F]FPIA uptake correlated positively with Ki-67 (p < 0.01), SLC22A5 (p < 0.001) and SLC25A20 (p = 0.001), and negatively with CPT1 (p < 0.01) and SLC22A2 (p < 0.01). Etomoxir reduced [18F]FPIA uptake, which correlated with decreased Ki-67 (p < 0.05).ConclusionsOur findings support the use of [18F]FPIA PET for the detection and longitudinal monitoring of glioma, showing a positive correlation with tumor proliferation, and suggest transcellular flux-mediated radiotracer uptake.
| S-EPMC8301305 | biostudies-literature
Project description:PurposeThe aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [18F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA).MethodsIn vivo positron emission tomography (PET) imaging with [18F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration.ResultsBased on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [18F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = - 0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [18F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman's ρ = 0.94; p = 0.005).ConclusionThese findings reveal that [18F]FEPPA PET is an effective marker for detecting increased CD68-positive microglial/macrophage activation and demonstrates sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.
| S-EPMC7410886 | biostudies-literature
Project description:Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L-type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion: 18F-FDOPA PET/CT complemented 18F-FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy.
| S-EPMC6167538 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) are now commonly used to treat patients with metastatic malignant melanoma. Although concerns have been raised that the inflammatory response induced by ICIs may limit the ability of 18F-FDG PET/CT to assess tumor response, systematic analyses on the use of 18F-FDG PET/CT in this setting are mostly lacking. Thus, we set out to evaluate the association between tumor response on 18F-FDG PET/CT and prognosis in patients with metastatic malignant melanoma treated with ipilimumab. Methods: We analyzed 60 consecutive patients with metastatic melanoma who underwent 18F-FDG PET/CT scans both before and after treatment to evaluate treatment response after completion of ipilimumab therapy. Tumor response was assessed by the change in the sum of SULpeak (voxels with the highest average SUL [SUV normalized to lean body mass]) of up to 5 lesions according to PERCIST5. New lesions on PET that appeared suggestive of metastases were considered progressive metabolic disease (PMD). Because immunotherapy may cause new inflammatory lesions that are detectable on 18F-FDG PET/CT, we also evaluated an immunotherapy-modified response classification (imPERCIST5). In this classification, new lesions do not define PMD per se; rather, PMD requires an increase in the sum of SULpeak by 30%. The correlation between tumor response according to these 3 definitions and overall survival (OS) was evaluated and compared with known prognostic factors. Results: In responders and nonresponders, the 2-y OS was 66% versus 29% for imPERCIST5 (P = 0.003). After multivariate analysis, imPERCIST5 remained prognostic (hazard ratio, 3.853; 95% confidence interval, 1.498-9.911; P = 0.005). New sites of focal 18F-FDG uptake occurred more often in patients with PMD (n = 24) by imPERCIST5 than in those with stable metabolic disease (n = 7) or partial metabolic response (n = 4). In patients with partial metabolic response, 2 of 4 isolated new lesions regressed spontaneously during follow-up. Conclusion: In patients with metastatic melanoma treated with ipilimumab, tumor response according to PERCIST was associated with OS. Our data suggest that PMD should not be defined by the appearance of new lesions, but rather by an increase in the sum of SULpeak.
| S-EPMC6424231 | biostudies-literature
Project description:PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5?±?2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0?±?2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p?<?0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5?±?0.2 compared to 1.3?±?0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7?±?2.3 h), and achieving a consistent final distribution volume averaging 1.4?±?0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57?±?51 min), with an average distribution volume of 3.2?±?1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.
| S-EPMC7188736 | biostudies-literature
Project description:O'nyong-nyong virus (ONNV) is an arthritogenic alphavirus that caused two large epidemics in 1959 and 1996, affecting millions of people in Africa. More recently, sero-surveillance of healthy blood donors conducted in 2019 revealed high rates of unreported ONNV infection in Uganda. Due to similar clinical symptoms with other endemic mosquito-borne pathogens in the region, including chikungunya virus, dengue virus and malaria, ONNV infections are often un- or misdiagnosed. Elucidating the immunopathogenic factors of this re-emerging arbovirus is critical with the expanding geographic distribution of competent vectors. This study reports the establishment of an immune competent C57BL6/J mouse model to mechanistically characterize ONNV infection and assess potential treatment efficacy. This mouse model successfully recapitulated arthralgia and viremia profiles seen in ONNV patients. Furthermore, longitudinal in-vivo PET imaging with [18F]FB-IL-2 (CD25+CD4+ binding probe) and histopathological assessment in this model demonstrated the pathogenic role of CD4+ T cells in driving joint pathology. Concordantly, in vivo CD4+ T cell depletion, or suppression with fingolimod, an FDA-approved immunomodulating drug, abrogated CD4+ T cell-mediated disease. This study demonstrates the importance of this immune competent ONNV model for future studies on factors influencing disease pathogenesis, which could shape the discovery of novel therapeutic strategies for arthritogenic alphaviruses.
| S-EPMC7235449 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18F-radiolabeled isotopolog of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18F-olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and 18F-olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of 18F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18F-olaparib increased by 70% (P = 0.025). Conclusion: Taken together, we show that 18F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.
| S-EPMC6448459 | biostudies-literature
Project description:BackgroundThe clinical diagnosis of deep sternal wound infection (DSWI) is supported by imaging findings including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). To avoid misinterpretation due to normal post-surgery inflammation we assessed normal imaging findings in non-infected patients after sternotomy.MethodsThis is a prospective cohort study including non-infectious patients with sternotomy. All patients underwent 18F-FDG-PET/CT at either 5 weeks (group 1), 12 weeks (group 2) or 52 weeks (group 3) post-surgery. 18F-FDG uptake was scored visually in five categories and assessed quantitatively.ResultsA total of 44 patients were included. Sternal mean SUVmax was 7.34 (± 1.86), 5.22 (± 2.55) and 3.20 (± 1.80) in group 1, 2 and 3, respectively (p < 0.01). Sternal mean SUVmean was 3.84 (± 1.00), 2.69 (± 1.32) and 1.71 (± 0.98) in group 1, 2 and 3 (p < 0.01). All patients in group 1 had elevated uptake whereas group 2 and 3 showed 2/15 (13%) and 11/20 (55%) patients respectively with no elevated uptake. Group 3 still showed an elevated uptake pattern in in 9/20 (45%) and in 3/9 (33%) with a high-grade diffuse uptake pattern.ConclusionThis study shows significant lower sternal 18F-FDG at 55 weeks compared to 5 weeks post-sternotomy however elevated uptake patterns may persist.
| S-EPMC10261398 | biostudies-literature
Project description:BackgroundMolecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL2) could be such a strategy. This paper describes the challenging translation of the partly manual labeling of [18F]FB-IL2 for preclinical studies into an automated procedure following Good Manufacturing Practices (GMP), resulting in a radiopharmaceutical suitable for clinical use.MethodsThe preclinical synthesis of [18F]FB-IL2 was the starting point for translation to a clinical production method. To overcome several challenges, major adaptations in the production process were executed. The final analytical methods and production method were validated and documented. All data with regards to the quality and safety of the final drug product were documented in an investigational medicinal product dossier.ResultsRestrictions in the [18F]FB-IL2 production were imposed by hardware configuration of the automated synthesis equipment and by use of disposable cassettes. Critical steps in the [18F]FB-IL2 production comprised the purification method, stability of recombinant human IL2 and the final formulation. With the GMP compliant production method, [18F]FB-IL2 could reliably be produced with consistent quality complying to all specifications.ConclusionsTo enable the use of [18F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. [18F]FB-IL2 is now produced consistently for use in clinical studies.
| S-EPMC6637160 | biostudies-literature
Project description:High liver uptake presents a problem for 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and β-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, β-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [18F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and β-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [18F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [18F]FLT slightly. The application of cold FLT reduced overall uptake of [18F]FLT including the liver background. Therefore, the combined application of cold FLT and [18F]FLT merits further clinical investigation for reducing liver background uptake of [18F]FLT.
| S-EPMC7675117 | biostudies-literature