Dataset Information

Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.

ABSTRACT: Pretargeting parameters for the use of anti-carcinoembryonic antigen (CEA) bispecific monoclonal antibody TF2 and the ⁶⁸Ga-labeled IMP288 peptide for immuno-PET have been optimized in a first-in-humans study performed on medullary thyroid carcinoma (MTC) patients (the iPET-MTC study). The aim of this post hoc analysis was to determine the sensitivity of immuno-PET in relapsing MTC patients, in comparison with conventional imaging and ¹⁸F-l-dihydroxyphenylalanine (¹⁸F-DOPA) PET/CT. Methods: Twenty-five studies were analyzed in 22 patients. All patients underwent immuno-PET 1 and 2 h after ⁶⁸Ga-IMP288 injection pretargeted by TF2, in addition to neck, thoracic, abdominal, and pelvic CT; bone and liver MRI; and ¹⁸F-DOPA PET/CT. The gold standard was histology or confirmation by one other imaging method or by imaging follow-up. Results: In total, 190 lesions were confirmed by the gold standard: 89 in lymph nodes, 14 in lungs, 46 in liver, 37 in bone, and 4 in other sites (subcutaneous tissue, heart, brain, and pancreas). The number of abnormal foci detected by immuno-PET was 210. Among these, 174 (83%) were confirmed as true-positive by the gold standard. Immuno-PET showed a higher overall sensitivity (92%) than ¹⁸F-DOPA PET/CT (65%). Regarding metastatic sites, immuno-PET had a higher sensitivity than CT, ¹⁸F-DOPA PET/CT, or MRI for lymph nodes (98% vs. 83% for CT and 70% for ¹⁸F-DOPA PET/CT), liver (98% vs. 87% for CT, 65% for ¹⁸F-DOPA PET/CT, and 89% for MRI), and bone (92% vs. 64% for ¹⁸F-DOPA PET/CT and 86% for MRI), whereas sensitivity was lower for lung metastases (29% vs. 100% for CT and 14% for ¹⁸F-DOPA PET/CT). Tumor SUV_max at 60 min ranged from 1.2 to 59.0, with intra- and interpatient variability. Conclusion: This post hoc study demonstrates that anti-carcinoembryonic antigen immuno-PET is an effective procedure for detecting metastatic MTC lesions. Immuno-PET showed a higher overall sensitivity than ¹⁸F-DOPA PET/CT for disclosing metastases, except for the lung, where CT remains the most effective examination.

SUBMITTER: Bodet-Milin C

PROVIDER: S-EPMC8882894 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.

Bodet-Milin Caroline C Faivre-Chauvet Alain A Carlier Thomas T Ansquer Catherine C Rauscher Aurore A Frampas Eric E Toulgoat Frederique F Masson Damien D Bourgeois Mickael M Cerato Evelyne E Rohmer Vincent V Couturier Olivier O Drui Delphine D Goldenberg David M DM Sharkey Robert M RM Barbet Jacques J Kraeber-Bodere Francoise F

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20210205 9

Pretargeting parameters for the use of anti-carcinoembryonic antigen (CEA) bispecific monoclonal antibody TF2 and the 68Ga-labeled IMP288 peptide for immuno-PET have been optimized in a first-in-humans study performed on medullary thyroid carcinoma (MTC) patients (the iPET-MTC study). The aim of this post hoc analysis was to determine the sensitivity of immuno-PET in relapsing MTC patients, in comparison with conventional imaging and 18F-l-dihydroxyphenylalanine (18</s ...[more]

PMID: 33547213

Similar Datasets

Project description:Unlabelled5B1 is a fully human, monoclonal antibody that has shown promise for the PET imaging of cancers expressing carbohydrate antigen 19.9 (CA19.9)--a carbohydrate prevalent in cells with aberrant glycosylation and an established effector of metastasis. The long physiologic half-life of the antibody and interference from circulating CA19.9 may increase the time required to generate quality images as well as the risk of radiation exposure to healthy tissues during repeated PET imaging. Pretargeting methodologies are an effective approach to expeditiously acquire PET images, but in this case, the pretargeting approach is complicated by the internalization of 5B1 by CA19.9-expressing cells. We sought to adapt and optimize a pretargeting strategy that exploits the bioorthogonal reaction between transcyclooctene (TCO) and tetrazine (Tz) to overcome these complications.Methods5B1 was modified with TCO, and a novel NOTA-PEG7-Tz radioligand was synthesized with the goal of improving on a previously reported analog. BxPC3 and Capan-2 cells were evaluated for their ability to internalize anti-CA19.9 antibodies using a fluorometric assay, and xenografts of the same lines were used for in vivo studies. The pretargeting approach was optimized, and the 2 radioligands were compared using biodistribution and PET imaging in murine models of pancreatic cancer.ResultsBxPC3 and Capan-2 cells were shown to rapidly internalize anti-CA19.9 monoclonal antibodies, including 5B1. (64)Cu-NOTA-PEG7-Tz showed improved in vivo pharmacokinetics relative to (64)Cu-NOTA-Tz using 5B1-TCO as the targeting vector. PET imaging and biodistribution studies showed that injecting the radioligand 72 h after the administration of 5B1-TCO resulted in the best uptake (8.2 ± 1.7 percentage injected dose per gram at 20 h after injection) and tumor-to-background activity concentration ratios. Dosimetry calculations revealed that the pretargeting system produced a greater than 25-fold reduction in total body radiation exposure relative to (89)Zr-desferrioxamine-5B1. PET/CT imaging in an orthotopic Capan-2 xenograft model--which secretes large amounts of CA19.9 and more rapidly internalizes anti-CA19.9 antibodies--showed that this approach is viable even in the difficult circumstances presented by a circulating antigen and internalized targeting vector.ConclusionThe 5B1-TCO and (64)Cu-NOTA-PEG7-Tz system evaluated in these studies can delineate CA19.9-positive xenografts in murine models of pancreatic cancer despite the challenges posed by the combination of circulating antigen and internalization of the 5B1-TCO.

Project description:The last decade has witnessed the creation of a highly effective approach to in vivo pretargeting based on the inverse electron demand Diels-Alder (IEDDA) click ligation between tetrazine (Tz) and trans-cyclooctene (TCO). Despite the steady progression of this technology toward the clinic, concerns have persisted regarding whether this in vivo chemistry will work in humans given their larger size and blood volume. In this work, we describe the use of a 64Cu-labeled Tz radioligand ([64Cu]Cu-SarAr-Tz) and a TCO-bearing bisphosphonate (TCO-BP) for the pretargeted positron emission tomography (PET) imaging of osteodestructive lesions in a large animal model: companion dogs. First, in a small animal pilot study, healthy mice were injected with TCO-BP followed after 1 or 6 h by [64Cu]Cu-SarAr-Tz. PET images were collected 1, 6, and 24 h after the administration of [64Cu]Cu-SarAr-Tz, revealing that this approach produced high activity concentrations in the bone (>20 and >15%ID/g in the femur and humerus, respectively, at 24 h post injection) as well as high target-to-background contrast. Subsequently, companion dogs (n = 5) presenting with osteodestructive lesions were administered TCO-BP (5 or 10 mg/kg) followed 1 h later by [64Cu]Cu-SarAr-Tz (2.2-7.3 mCi; 81.4-270.1 MBq). PET scans were collected for each dog 4 h after the administration of the radioligand, and SUV values for the osteodestructive lesions, healthy bones, and kidneys were determined. In these animals, pretargeted PET clearly delineated healthy bone and produced very high activity concentrations in osteodestructive lesions. Low levels of uptake were observed in all healthy organs except for the kidneys and bladder due to the renal excretion of excess radioligand. Ultimately, this work not only illustrates that pretargeted PET with TCO-BP and [64Cu]Cu-SarAr-Tz is an effective tool for the visualization of osteodestructive lesions but also demonstrates for the first time that in vivo pretargeting based on IEDDA click chemistry is feasible in large animals.

Project description:ObjectivesA phase I pretargeted radioimmunotherapy trial (EudractCT 200800603096) was designed in patients with metastatic lung cancer expressing carcinoembryonic antigen (CEA) to optimize bispecific antibody and labeled peptide doses, as well as the delay between their injections.MethodsThree cohorts of three patients received the anti-CEA × anti-histamine-succinyl-glycine (HSG)-humanized trivalent bispecific antibody (TF2) and the IMP288 bivalent HSG peptide. Patients underwent a pretherapeutic imaging session S1 (44 or 88 nmol/m(2) of TF2 followed by 4.4 nmol/m(2), 185 MBq, of (111)In-labeled IMP288) and, 1-2 weeks later, a therapy session S2 (240 or 480 nmol/m(2) of TF2 followed by 24 nmol/m(2), 1.1 GBq/m(2), of (177)Lu-labeled IMP288). The pretargeting delay was 24 or 48 h. The dose schedule was defined based on preclinical TF2 pharmacokinetic (PK) studies, on our previous clinical data using the previous anti-CEA-pretargeting system, and on clinical results observed in the first patients injected using the same system in Netherlands.ResultsTF2 PK was represented by a two-compartment model in which the central compartment volume (Vc) was linearly dependent on the patient's surface area. PK was remarkably similar, with a clearance of 0.33 ± 0.03 L/h/m(2). (111)In- and (177)Lu-IMP288 PK was also well represented by a two-compartment model. IMP288 PK was faster (clearance 1.4-3.3 L/h). The Vc was proportional to body surface area, and IMP288 clearance depended on the molar ratio of injected IMP288 to circulating TF2 at the time of IMP288 injection. Modeling of image quantification confirmed the dependence of IMP288 kinetics on circulating TF2, but tumor activity PK was variable. Organ-absorbed doses were not significantly different in the three cohorts, but the tumor dose was significantly higher with the higher molar doses of TF2 (p < 0.002). S1 imaging predicted absorbed doses calculated in S2.ConclusionThe best dosing parameters corresponded to the shorter pretargeting delay and to the highest TF2 molar doses. S1 imaging session accurately predicted PK as well as absorbed doses of S2, thus potentially allowing for patient selection and dose optimization.Trial registrationClinicalTrials.gov NCT01221675 (EudractCT 200800603096).

Project description:ObjectiveCorrect diagnosis and prognostic evaluation of medullary thyroid cancer (MTC) are crucial to treat patients. The purpose of this study was to evaluate the diagnostic and prognostic value of [18F]F-DOPA PET/CT in patients with MTC.MethodsWe reviewed MTC patients who underwent [18F]F-DOPA PET/CT from June 2008 to November 2023. Clinical characteristics, follow-up data, and the following [18F]F-DOPA PET/CT parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and SUVmean of multiple organs. The diagnostic value of PET/CT for the detection of tumor lesions was calculated. Serum basal calcitonin (bCt) and stimulated calcitonin (sCt) were determined. Receiver operating characteristics, Kaplan-Meier, and Cox regression analyses were performed.ResultsIn total, 109 patients (50 women, 59 men; average age, 55 ± 14 years) were included in the analysis. The patient-related sensitivity, specificity, and accuracy of [18F]F-DOPA PET/CT were 95%, 93%, and 94%, respectively. The lesion-related sensitivity, specificity, and accuracy were 65%, 99%, and 72%, respectively. The optimal cutoff values of bCt, sCt, and CEA to obtain positive [18F]F-DOPA PET/CT results were 64 pg/mL, 1808 pg/mL, and 4 µg/L, respectively. Patients with negative [18F]F-DOPA PET/CT had longer overall survival than patients with positive [18F]F-DOPA PET/CT results (P = 0.017). Significant positive correlations were found between bCt, sCt, and CEA with SUVmax, SUVmean, and MTV of [18F]F-DOPA PET/CT (P < 0.001). [18F]F-DOPA PET/CT results and MTV may be useful for the evaluation of the prognosis of patients with recurrent MTC, while age and MTV were independent prognostic factors in patients with primary MTC. For all patients, SUVmean of the left kidney, liver, aorta, and pancreas might be used to independently predict OS.Conclusion[18F]F-DOPA PET/CT had great value for diagnosis and prognostic assessment in patients with MTC. The DOPA PET/CT parameter SUVmean and MTV showed significant association with OS.

Dataset Information

Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.

Publications

Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets