ABSTRACT
BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.
Subject(s)
Intracellular Signaling Peptides and Proteins , Lung Neoplasms , Membrane Proteins , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms , Radioisotopes , Zirconium , Humans , Male , Middle Aged , Aged , Membrane Proteins/immunology , Membrane Proteins/metabolism , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/immunology , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/immunology , Neuroendocrine Tumors/diagnostic imaging , Neuroendocrine Tumors/pathology , Neuroendocrine Tumors/immunology , Neuroendocrine Tumors/drug therapy , Female , Deferoxamine/chemistry , Immunoconjugates/pharmacokinetics , Neoplasm Grading , Radiopharmaceuticals , Adult , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/administration & dosage , Aged, 80 and over , Benzodiazepinones , Antibodies, Monoclonal, HumanizedABSTRACT
PURPOSE: Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC. METHODS: SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [177Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [177Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice. RESULTS: H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [177Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [177Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome. CONCLUSION: The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.
ABSTRACT
BACKGROUND: This study aimed to assess the impact of dedicated cardiac protocol (DCP) on diagnostic accuracy of state-of-the-art digital [18F]-FDG-PET/CT in infective endocarditis (IE) and the intra-individual comparison of the performance with that of conventional whole-body approach (WBA) and to analyze the effects of the expertise level of the investigators. METHODS: 44 patients suspected for IE underwent digital-FDG-PET/CT after overnight fasting. Each three consultants and trainees reread PET images blinded to the examination approach and clinical information. Visual and semiquantitative analyses were performed. RESULTS: Digital-FDG-PET/CT with DCP revealed sensitivity, specificity, and accuracy of 89%, 93%, and 91% for native valve endocarditis (NVE) and 93%, 86%, and 91% for prosthetic valve endocarditis. Compared to WBA, substantial improvement of the diagnostic performance for NVE in DCP was evident, especially in trainees, but not as high compared to consultants. Digital-FDG-PET/CT enabled 79.5% reclassification of modified-Duke-Clinical-Criteria (mDC) with 34.1% upgrading and 45.4% downgrading. CONCLUSIONS: This study provides new data using state-of-the-art digital-FDG-PET/CT with DCP improving the diagnostic accuracy in challenging cases of possible IE, particularly in NVE, provided that the investigators involved have the necessary expertise. These findings may have a significant impact on IE-related morbidity, mortality, and patient's management and might be meaningful for updates on the prevailing opinion regarding the value of FDG PET/CT in NVE.
ABSTRACT
The demand for PET tracers that target prostate-specific membrane antigen (PSMA) continues to increase. Meeting this demand with approved 68Ga- and 18F-labeled PSMA tracers is challenging outside of major urban centers. This is because the short physical half-life of these radionuclides makes it necessary to produce them near their sites of usage. To overcome this challenge, we propose cyclotron-produced 61Cu for labeling PSMA PET tracers. 61Cu can be produced on a large scale, and its 3.33-h half-life allows shipping over considerably longer distances than possible for 68Ga and 18F. Production of true theranostic twins using 61Cu and the ß--emitter 67Cu is also feasible. Methods: PSMA-I&T (DOTAGA-(l-y)fk(sub-KuE)) and its derivative in which the DOTAGA chelator was replaced by NODAGA (NODAGA-(l-y)fk(sub-KuE)), herein reported as DOTAGA-PSMA-I&T and NODAGA-PSMA-I&T, respectively, were labeled with 61Cu and compared with [68Ga]Ga-DOTAGA-PSMA-I&T, [68Ga]Ga-NODAGA-PSMA-I&T, [68Ga]Ga-PSMA-11, and [18F]PSMA-1007. In vitro (lipophilicity, affinity, cellular uptake, and distribution) and in vivo (PET/CT, biodistribution, and stability) studies were performed in LNCaP cells and xenografts. Human dosimetry estimates were calculated for [61Cu]Cu-NODAGA-PSMA-I&T. First-in-human imaging with [61Cu]Cu-NODAGA-PSMA-I&T was performed in a patient with metastatic prostate cancer. Results: [61Cu]Cu-DOTAGA-PSMA-I&T and [61Cu]Cu-NODAGA-PSMA-I&T were synthesized with radiochemical purity of more than 97%, at an apparent molar activity of 24 MBq/nmol, without purification after labeling. In vitro, natural Cu (natCu)-DOTAGA-PSMA-I&T and natCu-NODAGA-PSMA-I&T showed high affinity for PSMA (inhibitory concentration of 50%, 11.2 ± 2.3 and 9.3 ± 1.8 nM, respectively), although lower than the reference natGa-PSMA-11 (inhibitory concentration of 50%, 2.4 ± 0.4 nM). Their cellular uptake and distribution were comparable to those of [68Ga]Ga-PSMA-11. In vivo, [61Cu]Cu-NODAGA-PSMA-I&T showed significantly lower uptake in nontargeted tissues than [61Cu]Cu-DOTAGA-PSMA-I&T and higher tumor uptake (14.0 ± 5.0 percentage injected activity per gram of tissue [%IA/g]) than [61Cu]Cu-DOTAGA-PSMA-I&T (6.06 ± 0.25 %IA/g, P = 0.0059), [68Ga]Ga-PSMA-11 (10.2 ± 1.5 %IA/g, P = 0.0972), and [18F]PSMA-1007 (9.70 ± 2.57 %IA/g, P = 0.080) at 1 h after injection. Tumor uptake was also higher for [61Cu]Cu-NODAGA-PSMA-I&T at 4 h after injection (10.7 ± 3.3 %IA/g) than for [61Cu]Cu-DOTAGA-PSMA-I&T (4.88 ± 0.63 %IA/g, P = 0.0014) and [18F]PSMA-1007 (6.28 ± 2.19 %IA/g, P = 0.0145). Tumor-to-nontumor ratios of [61Cu]Cu-NODAGA-PSMA-I&T were superior to those of [61Cu]Cu-DOTAGA-PSMA-I&T and comparable to those of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 at 1 h after injection and increased significantly between 1 and 4 h after injection in most cases. Human dosimetry estimates for [61Cu]Cu-NODAGA-PSMA-I&T were similar to the ones reported for 18F-PSMA ligands. First-in-human imaging demonstrated multifocal osseous and hepatic metastases. Conclusion: [61Cu]Cu-NODAGA-PSMA-I&T is a promising PSMA radiotracer that compares favorably with [68Ga]Ga-PSMA-11 and [18F]PSMA-1007, while allowing delayed imaging.
Subject(s)
Antigens, Surface , Copper Radioisotopes , Glutamate Carboxypeptidase II , Positron-Emission Tomography , Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Positron-Emission Tomography/methods , Glutamate Carboxypeptidase II/metabolism , Antigens, Surface/metabolism , Animals , Radioactive Tracers , Mice , Cell Line, Tumor , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemistry , Positron Emission Tomography Computed Tomography/methods , Tissue Distribution , Isotope LabelingABSTRACT
Prospective results have demonstrated favorable safety and efficacy of [177Lu]Lu-PSMA radiopharmaceutical therapy for up to 6 cycles in men with metastatic castration-resistant prostate cancer. However, no systematic data are available outlining the feasibility of extended therapy beyond 6 cycles. We aim to evaluate the safety and efficacy of extended [177Lu]Lu-PSMA radiopharmaceutical therapy in patients who have received more than 6 cycles. Methods: In total, 111 patients were included in this multicenter retrospective analysis. Based on individual decisions, patients underwent uninterrupted continuation of therapy (continuous treatment) or reexposure after a therapy break (rechallenge treatment) between 2014 and 2023. Overall survival, 50% prostate-specific antigen (PSA) decline (measured 8-12 wk after treatment initiation or rechallenge), PSMA PET response, and grades per Common Terminology Criteria for Adverse Events were assessed. χ2 tests, multivariable Cox regression analysis, and log-rank tests were applied for statistical analyses. Results: Patients received extended treatment with [177Lu]Lu-PSMA, either as a continuous treatment (43/111, 38.7%) or as a rechallenge (68/111, 61.3%) treatment, with median cumulative doses of 57.4 or 60.8 GBq, respectively. Overall survival from the initiation of [177Lu]Lu-PSMA was 31.3, 23.2, and 40.2 mo for the entire cohort, the continuous treatment group, and the rechallenge treatment group, respectively. The initial 50% PSA decline was significantly higher in the retreated group than in the continuous group (57/63 [90.4%] vs. 26/42 [61.9%]; P = 0.006). A 50% PSA decline was observed in 23 of 62 patients (37.1%) after the first rechallenge. The rate of grades 3-4 toxicity was comparable between continuous and rechallenge treatments (anemia, 7/43 [16.3%] vs. 13/68 [19.1%)], P = 0.6; leukocytopenia, 1/43 [2.3%] vs. 2/67 [3.0%], P = 0.3; thrombocytopenia, 3/43 [7.0%] vs. 3/68 [4.4%], P = 0.3; renal, 2/43 [4.7%] vs. 5/68 [7.4%], P = 0.2). Conclusion: Extended therapy with [177Lu]Lu-PSMA is safe and has not been associated with increased grades 3-4 toxicity. Patient candidates for extended treatment experienced a favorable median survival of 31.3 mo from the first administration. Response under [177Lu]Lu-PSMA rechallenge demonstrated preserved efficacy of [177Lu]Lu-PSMA after a treatment break.
Subject(s)
Lutetium , Humans , Male , Aged , Lutetium/therapeutic use , Retrospective Studies , Middle Aged , Treatment Outcome , Germany , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Prostatic Neoplasms, Castration-Resistant/pathology , Aged, 80 and over , Safety , Radiopharmaceuticals/therapeutic use , Radiopharmaceuticals/adverse effects , Prostate-Specific Antigen , RadioisotopesABSTRACT
PURPOSE: 68Ga-Trivehexin is an investigational PET radiopharmaceutical (NCT05799274) targeting αvß6-integrin for PET imaging of carcinomas. 177Lu-D0301 is a structurally related therapeutic peptide tetramer. However, it showed considerable kidney uptake in rodents, impeding clinical applicability. We therefore evaluated the impact of different kidney protection strategies on the biodistribution of both agents in normal and tumor-bearing mice. METHODS: Ex-vivo biodistribution of 68Ga-Trivehexin (90 min p.i.) and 177Lu-D0301 (90 min and 24 h p.i.) was determined in healthy C57BL/6N and H2009 (human lung adenocarcinoma) xenografted CB17-SCID mice without and with co-infusion of 100 µL of solutions containing 2.5% arginine + 2.5% lysine (Arg/Lys), 4% succinylated gelatin (gelofusine, gelo), or combinations thereof. Arg/Lys was injected either i.p. 30 min before and after the radiopharmaceutical, or i.v. 2 min before the radiopharmaceutical. Gelo was administered either i.v. 2 min prior activity, or pre-mixed and injected together with the radiopharmaceutical (n = 5 per group). C57BL/6N mice were furthermore imaged by PET (90 min p.i.) and SPECT (24 h p.i.). RESULTS: Kidney uptake of 68Ga-Trivehexin in C57BL/6N mice was reduced by 15% (Arg/Lys i.p.), 25% (Arg/Lys i.v.), and 70% (gelo i.v.), 90 min p.i., relative to control. 177Lu-D0301 kidney uptake was reduced by 2% (Arg/Lys i.p.), 41% (Arg/Lys i.v.), 61% (gelo i.v.) and 66% (gelo + Arg/Lys i.v.) 24 h p.i., compared to control. Combination of Arg/Lys and gelo provided no substantial benefit. Gelo furthermore reduced kidney uptake of 177Lu-D0301 by 76% (90 min p.i.) and 85% (24 h p.i.) in H2009 bearing SCID mice. Since tumor uptake was not (90 min p.i.) or only slightly reduced (15%, 24 h p.i.), the tumor/kidney ratio was improved by factors of 3.3 (90 min p.i.) and 2.6 (24 h p.i.). Reduction of kidney uptake was demonstrated by SPECT, which also showed that the remaining activity was located in the cortex. CONCLUSIONS: The kidney uptake of both investigated radiopharmaceuticals was more efficiently reduced by gelofusine (61-85%) than Arg/Lys (25-41%). Gelofusine appears particularly suitable for reducing renal uptake of αvß6-integrin targeted 177Lu-labeled peptide multimers because its application led to approximately three times higher tumor-to-kidney ratios. Since the incidence of severe adverse events (anaphylaxis) with succinylated gelatin products (reportedly 0.0062-0.038%) is comparable to that of gadolinium-based MRI or iodinated CT contrast agents (0.008% and 0.04%, respectively), clinical use of gelofusine during radioligand therapy appears feasible if similar risk management strategies as for contrast agents are applied.
Subject(s)
Gelatin , Integrins , Kidney , Animals , Mice , Kidney/metabolism , Kidney/diagnostic imaging , Tissue Distribution , Humans , Integrins/metabolism , Gelatin/chemistry , Radiopharmaceuticals/pharmacokinetics , Isotope Labeling , Cell Line, Tumor , Gallium Radioisotopes , Amino Acids/chemistry , Amino Acids/pharmacokinetics , Biological Transport , Peptides/pharmacokinetics , Peptides/chemistry , Safety , Mice, Inbred C57BL , Lutetium , Positron-Emission Tomography , Antigens, Neoplasm , Radioisotopes , SuccinatesABSTRACT
Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.
Subject(s)
Neoplasms , Precision Medicine , Theranostic Nanomedicine , Humans , Neoplasms/therapy , Neoplasms/diagnosis , Theranostic Nanomedicine/methods , Precision Medicine/methods , Drug Delivery Systems/methods , Nanomedicine/methods , History, 20th Century , Animals , History, 21st CenturyABSTRACT
Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Myocardial fibrosis plays an important role in adverse outcomes such as heart failure and arrhythmias. As the pathological response and degree of scarring, and therefore clinical presentation varies from patient to patient, early detection of fibrosis is crucial for identifying the appropriate treatment approach and forecasting the progression of a disease along with the likelihood of disease-related mortality. Current imaging modalities provides information about either decreased function or extracellular signs of fibrosis. Targeting activated fibroblasts represents a burgeoning approach that could offer insights prior to observable functional alterations, presenting a promising focus for potential anti-fibrotic therapeutic interventions at cellular level. In this article, we provide an overview of imaging cardiac fibrosis and discuss the role of different advanced imaging modalities with the focus on novel non-invasive imaging of activated fibroblasts.
Subject(s)
Fibrosis , Humans , Animals , Extracellular Space/metabolism , Extracellular Space/diagnostic imaging , Fibroblasts/metabolism , Myocardium/pathology , Myocardium/metabolism , Diagnostic Imaging/methodsABSTRACT
Background: Delta-like ligand 3 (DLL3) is aberrantly expressed on the cell surface in many neuroendocrine cancers including small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Several therapeutic agents targeting DLL3 are in active clinical development. Molecular imaging of DLL3 would enable non-invasive diagnostic assessment to inform the use of DLL3-targeting therapeutics or to assess disease treatment response. Methods: We conducted a first-in-human immuno-positron emission tomography (immunoPET) imaging study of [89Zr]Zr-DFO-SC16.56, composed of the anti-DLL3 antibody SC16.56 conjugated to desferrioxamine (DFO) and the positron-emitting radionuclide zirconium-89, in 18 patients with neuroendocrine cancers. An initial cohort of three patients received 1-2 mCi of [89Zr]Zr-DFO-SC16.56 at a total mass dose of 2·5 mg and underwent serial PET and computed tomography (CT) imaging over the course of one week. Radiotracer clearance, tumor uptake, and radiation dosimetry were estimated. An expansion cohort of 15 additional patients were imaged using the initial activity and mass dose. Retrospectively collected tumor biopsies were assessed for DLL3 by immunohistochemistry (IHC) (n = 16). Findings: Imaging of the initial 3 SCLC patients demonstrated strong tumor-specific uptake of [89Zr]Zr-DFO-SC16.56, with similar tumor: background ratios at days 3, 4, and 7 post-injection. Serum clearance was bi-phasic with an estimated terminal clearance half-time of 119 h. The sites of highest background tracer uptake were blood pool and liver. The normal tissue receiving the highest radiation dose was liver; 1·8 mGy/MBq, and the effective dose was 0.49 mSv/MBq. Tumoral uptake varied both between and within patients, and across anatomic sites, with a wide range in SUVmax (from 3·3 to 66·7). Tumor uptake by [89Zr]Zr-DFO-SC16.56 was associated with protein expression in all cases. Two non-avid DLL3 NEPC cases by PET scanning demonstrated the lowest DLL3 expression by tumor immunohistochemistry. Only one patient had a grade 1 allergic reaction, while no grade ≥2 adverse events noted. Interpretation: DLL3 PET imaging of patients with neuroendocrine cancers is safe and feasible. These results demonstrate the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in vivo detection of DLL3-expressing malignancies. Funding: Supported by NIH R01CA213448 (JTP), R35 CA263816 (CMR), U24 CA213274 (CMR), R35 CA232130 (JSL), and a Prostate Cancer Foundation TACTICAL Award (JSL), Scannell foundation. The Radiochemistry and Molecular Imaging Probes Core Facility is supported by NIH P30 CA08748.
ABSTRACT
ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Male , Humans , Retrospective Studies , Treatment Outcome , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Prostatic Neoplasms, Castration-Resistant/pathology , Prostate-Specific Antigen , Dipeptides/adverse effects , Lutetium/adverse effects , Heterocyclic Compounds, 1-Ring/adverse effectsABSTRACT
Most Prostate Specific Membrane Antigens (PSMAs) targeting small molecules accumulate in the salivary glands (SGs), raising concerns about SG toxicity, especially after repeated therapies or therapy with 225Ac-labeled ligands. SG toxicity is assessed clinically by the severity of patient-reported xerostomia, but this parameter can be challenging to objectively quantify. Therefore, we explored the feasibility of using SG volume as a biomarker for toxicity. In 21 patients with late-stage metastatic resistant prostate cancer (mCRPC), the PSMA volume and ligand uptake of SG were analyzed retrospectively before and after two cycles of 177Lu-PSMA (LuPSMA; cohort A) and before and after one cycle of 225Ac-PSMA-617 (AcPSMA, cohort B). Mean Volume-SG in cohort A was 59 ± 13 vs. 54 ± 16 mL (-10%, p = 0.4), and in cohort B, it was 50 ± 13 vs. 40 ± 11 mL (-20%, p = 0.007), respectively. A statistically significant decrease in the activity concentration in the SG was only observed in group B (SUVmean: 9.2 ± 2.8 vs. 5.3 ± 1.8, p < 0.0001; vs. A: SUVmean: 11.2 ± 3.3 vs. 11.1 ± 3.5, p = 0.8). SG volume and PSMA-ligand uptake are promising markers to monitor the SG toxicity after a PSMA RLT.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Xerostomia , Humans , Male , Heterocyclic Compounds, 1-Ring/therapeutic use , Ligands , Lutetium/therapeutic use , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Salivary Glands/pathology , Treatment OutcomeABSTRACT
BACKGROUND: Targeting prostate-specific membrane antigen (PSMA) has been highly successful for imaging and treatment of prostate cancer. However, heterogeneity in immunohistochemistry indicates limitations in the effect of imaging and radionuclide therapy of multifocal disease. 99mTc-PSMA-I&S is a γ-emitting probe, which can be used for intraoperative lesion detection and postsurgical autoradiography (ARG). We aimed to study its intraprostatic distribution and compared it with (immuno)-histopathology. RESULTS: Seventeen patients who underwent RGS between 11/2018 and 01/2020 with a total of 4660 grids were included in the preliminary analysis. Marked intratumor and intra-patient heterogeneity of PSMA expression was detected, and PSMA negative foci were observed in all samples (100%). Heterogeneous intra-patient PSMA-ligand uptake was observed, and no significant correlation was present between the degree of heterogeneity of PSMA expression and PSMA-ligand uptake. Higher PSMA-ligand uptake was observed in GS ≥ 8 than GS < 8 (p < 0.001). The appearance of Gleason Pattern (GP) 4 was strongly associated with higher uptake (coefficient: 0.43, p < 0.001), while GP 5 also affected the uptake (coefficient: 0.07, p < 0.001). CONCLUSION: PSMA expression and PSMA-ligand uptake show marked heterogeneity. Prostate carcinoma with GP 4 showed significantly higher uptake compared with non-neoplastic prostate tissue. Our analyses extend the scope of applications of radiolabeled PSMA-ligands to ARG for identifying high-grade disease and using its signal as a noninvasive biomarker in prostate cancer.
ABSTRACT
PURPOSE: 131I-MIP-1095 is a targeted radiotherapeutic that contains 131I, a ß-particle emitter, and MIP-1095, a urea-based ligand for prostate-specific membrane antigen. We report the first phase 1, dose-escalation study of 131I-MIP-1095 in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study enrolled men with mCRPC refractory to second-generation antiandrogen(s) and taxane chemotherapy. Dosimetry/biodistribution assessments were performed. Safety and tolerability were determined in subjects who qualified for therapeutic administration of 131I-MIP-1095 with maximum tolerated activity examined in a dose-ascending manner (3 + 3 design methodology). Disease outcomes including prostate-specific antigen (PSA) change, tumor response, survival, and circulating tumor cell concentration were assessed. RESULTS: A total of 9 subjects with mCRPC were included in this study. On the basis of dosimetry results, 5 of 9 patients were treated: 3 in cohort 1 (50 mCi) and 2 in cohort 2 (75 mCi). Accrual stopped at the cohort 2 activity level in response to the US Food and Drug Administration mandate for 131I-MIP-1095 manufacturing concerns. Parotid/salivary glands (3.5 Gy/Bq), liver (2.2 Gy/Bq), kidneys (1.3 Gy/Bq), and spleen (0.7 Gy/Bq) demonstrated the greatest extent of 131I-MIP-1095 exposure. There were no deaths, serious adverse events, or drug discontinuations due to treatment-emergent adverse events. Grade 1-2 thrombocytopenia, anemia, leukopenia, and dry mouth most commonly occurred. One subject (33.3%) exhibited maximum decline for the PSA response of 50% or greater. CONCLUSION: 131I-MIP-1095 demonstrated favorable dosimetry, biodistribution, and safety, as well as a modest PSA response supporting further investigation for treatment of men with mCRPC.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03030885, Registered January 25, 2017 (https://clinicaltrials.gov/ct2/show/NCT03030885).
Subject(s)
Antineoplastic Agents , Prostatic Neoplasms, Castration-Resistant , Humans , Male , Antineoplastic Agents/adverse effects , Iodine Radioisotopes/adverse effects , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/drug therapy , Radiopharmaceuticals/adverse effects , Tissue Distribution , Treatment OutcomeABSTRACT
New treatment strategies are urgently needed for glioblastoma (GBM)-a tumor resistant to standard-of-care treatment with a high risk of recurrence and extremely poor prognosis. Based on their intrinsic tumor tropism, adoptively applied mesenchymal stem cells (MSCs) can be harnessed to deliver the theranostic sodium/iodide symporter (NIS) deep into the tumor microenvironment. Interleukin-6 (IL-6) is a multifunctional, highly expressed cytokine in the GBM microenvironment including recruited MSCs. MSCs engineered to drive NIS expression in response to IL-6 promoter activation offer the possibility of a new tumor-targeted gene therapy approach of GBM. Therefore, MSCs were stably transfected with an NIS-expressing plasmid controlled by the human IL-6 promoter (IL-6-NIS-MSCs) and systemically applied in mice carrying orthotopic GBM. Enhanced radiotracer uptake by 18F-Tetrafluoroborate-PET/magnetic resonance imaging (MRI) was detected in tumors after IL-6-NIS-MSC application as compared with mice that received wild-type MSCs. Ex vivo analysis of tumors and non-target organs showed tumor-specific NIS protein expression. Subsequent 131I therapy after IL-6-NIS-MSC application resulted in significantly delayed tumor growth assessed by MRI and improved median survival up to 60% of GBM-bearing mice as compared with controls. In conclusion, the application of MSC-mediated NIS gene therapy focusing on IL-6 biology-induced NIS transgene expression represents a promising approach for GBM treatment.
ABSTRACT
The aim of this retrospective analysis was to evaluate health-related quality of life (HRQoL) for patients with metastatic castration-resistant prostate cancer (mCRPC) receiving consecutive cycles of 177Lu-prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) using the reliable and validated European Organisation for Research and Treatment of Cancer core quality-of-life (QoL) questionnaire. In addition, differences in HRQoL between patients with early discontinuation of treatment because of disease progression and patients who were defined as eligible for treatment continuation were analyzed. Methods: In total, 60 mCRPC patients were included in this analysis. The European Organisation for Research and Treatment of Cancer core QoL questionnaire was completed at baseline, before each treatment cycle up to the sixth treatment cycle, and at the time of PSMA-ligand PET/CT scans after the second and fourth treatment cycles. QoL assessment included global health status, functional scales, and symptom burden during treatment. Results: Global health was significantly improved at the second and fourth cycles of 177Lu-PSMA RLT (P = 0.014 and P = 0.039, respectively). In line with this, role and emotional functioning showed significant improvements at the second and fourth treatment cycles (role functioning, P = 0.045 and P = 0.048, respectively, and emotional functioning, P = 0.035 and P = 0.007, respectively). In addition, compared with baseline, fatigue and pain were significantly alleviated at the second and fourth treatment cycles (pain, P = 0.035 and P = 0.034, respectively, and fatigue, P = 0.042 and P = 0.041, respectively). Other aspects of HRQoL, even if not significantly improved, remained stable over time, except for deterioration of fatigue at the study's end (P = 0.014) and reduction of dyspnea at the second treatment cycle (P = 0.012). Patients with early discontinuation of treatment showed a concordant decline in HRQoL. Conclusion: mCRPC patients showed significant improvement in HRQoL in the course of treatment with 177Lu-PSMA RLT. Furthermore, patients with early discontinuation of treatment showed an analogous decline in HRQoL.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Quality of Life , Humans , Male , Dipeptides/therapeutic use , Heterocyclic Compounds, 1-Ring/therapeutic use , Lutetium/therapeutic use , Pain , Positron Emission Tomography Computed Tomography , Prostate-Specific Antigen , Prostatic Neoplasms, Castration-Resistant/radiotherapy , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Treatment OutcomeSubject(s)
Prostatic Neoplasms , Male , Humans , Prostatic Neoplasms/diagnostic imaging , Prostate-Specific AntigenABSTRACT
Prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) has shown encouraging results for treatment of metastatic castration-resistant prostate cancer (mCRPC) in the prospective, multicenter, randomized phase II TheraP study. The inclusion criteria for that study comprised a pretherapeutic 68Ga-PSMA-11 PET scan showing sufficient tumor uptake using a predefined threshold and the absence of 18F-FDG-positive, PSMA ligand-negative tumor lesions. However, the prognostic value of these PET-based inclusion criteria remains unclear. Therefore, we evaluated the outcome of mCRPC patients treated with PSMA RLT using TheraP as well as other TheraP-based PET inclusion criteria. Methods: First, patients were dichotomized into 2 groups whose PSMA PET scans did (TheraP contrast-enhanced PSMA [cePSMA] PET-positive) or did not (TheraP cePSMA PET-negative) fulfill the inclusion criteria of TheraP. Notably, unlike in TheraP, 18F-FDG PET was not performed on our patients. Prostate-specific antigen (PSA) response (PSA decline ≥ 50% from baseline), PSA progression-free survival, and overall survival (OS) were compared. Additionally, patients were further dichotomized according to predefined SUVmax thresholds different from those used in TheraP to analyze their potential impact on outcome as well. Results: In total, 107 mCRPC patients were included in this analysis (TheraP cePSMA PET-positive, n = 77; TheraP cePSMA PET-negative, n = 30). PSA response rates were higher in TheraP cePSMA PET-positive patients than in TheraP cePSMA PET-negative patients (54.5% vs. 20%, respectively; P = 0.0012). The median PSA progression-free survival (P = 0.007) and OS (P = 0.0007) of patients were significantly longer in the TheraP cePSMA PET-positive group than in the TheraP cePSMA PET-negative group. Moreover, being in the TheraP cePSMA PET-positive group was identified as a significant prognosticator of longer OS (P = 0.003). The application of different SUVmax thresholds for a single hottest lesion demonstrated no influence on outcome in patients eligible for PSMA RLT. Conclusion: Patient selection for PSMA RLT according to the inclusion criteria of TheraP led to a better treatment response and outcome in our preselected patient cohort. However, a relevant number of patients not fulfilling these criteria also showed substantial rates of response.