RESUMO
PURPOSE: The aim of this study was to evaluate the efficacy and safety of peptide-targeted radionuclide therapy (PTRT) with 177Lu-FAP-2286 in advanced lung cancer. PATIENTS AND METHODS: This single-center prospective study included 9 patients diagnosed with advanced lung cancer. These patients met the inclusion criteria and received PTRT with 177Lu-FAP-2286. Short-term efficacy was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Long-term efficacy was evaluated through overall survival, progression-free survival (PFS), overall response rate, EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status. Toxicity response was assessed using CTCAE v5.0. RESULTS: The results based on RECIST 1.1 and PERCIST 1.0 criteria were comparable, with 44% of patients showing a partial metabolic response, 33.3% with stable metabolic disease, and 22.22% with progressive metabolic disease. The highest metabolic response after treatment reached 66.89%, and the overall response rate could reach 77.78%. In the long-term efficacy assessment, the median overall survival and PFS were 10 months and 6 months, respectively. The 2 patients with the lowest PFS (3 months) started PTRT relatively late. EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status scores showed that the overall health status, symptom response, and quality of life of patients improved after 177Lu-FAP-2286 treatment. The most noticeable improvements in clinical symptoms were dyspnea and cancer-related pain. No grade III/IV toxicity events were observed during follow-up period, and fibrinogen decreased significantly after treatment. CONCLUSIONS: 177Lu-FAP-2286 has the potential to be a viable PTRT option for patients with advanced lung cancer.
Assuntos
Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Pulmonares/radioterapia , Feminino , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Lutécio/uso terapêutico , SegurançaRESUMO
Background Lutetium 177 [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC). Quantitative PSMA PET/CT analysis could provide information on 177Lu-PSMA-617 treatment benefits. Purpose To explore the association between quantitative baseline gallium 68 [68Ga]Ga-PSMA-11 (68Ga-PSMA-11) PET/CT parameters and treatment response and outcomes in the VISION trial. Materials and Methods This was an exploratory secondary analysis of the VISION trial. Eligible participants were randomized (June 2018 to October 2019) in a 2:1 ratio to 177Lu-PSMA-617 therapy (7.4 GBq every 6 weeks for up to six cycles) plus standard of care (SOC) or to SOC only. Baseline 68Ga-PSMA-11 PET parameters, including the mean and maximum standardized uptake value (SUVmean and SUVmax), PSMA-positive tumor volume, and tumor load, were extracted from five anatomic regions and the whole body. Associations of quantitative PET parameters with radiographic progression-free survival (rPFS), overall survival (OS), objective response rate, and prostate-specific antigen response were investigated using univariable and multivariable analyses (with treatment as the only other covariate). Outcomes were assessed in subgroups based on SUVmean quartiles. Results Quantitative PET parameters were well balanced between study arms for the 826 participants included. The median whole-body tumor SUVmean was 7.6 (IQR, 5.8-9.9). Whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy, with a hazard ratio (HR) range of 0.86-1.43 for all outcomes (all P < .001). A 1-unit whole-body tumor SUVmean increase was associated with a 12% and 10% decrease in risk of an rPFS event and death, respectively. 177Lu-PSMA-617 plus SOC prolonged rPFS and OS in all SUVmean quartiles versus SOC only, with no identifiable optimum among participants receiving 177Lu-PSMA-617. Higher baseline PSMA-positive tumor volume and tumor load were associated with worse rPFS (HR range, 1.44-1.53 [P < .05] and 1.02-1.03 [P < .001], respectively) and OS (HR range, 1.36-2.12 [P < .006] and 1.04 [P < .001], respectively). Conclusion Baseline 68Ga-PSMA-11 PET/CT whole-body tumor SUVmean was the best predictor of 177Lu-PSMA-617 efficacy in participants in the VISION trial. Improvements in rPFS and OS with 177Lu-PSMA-617 plus SOC were greater among participants with higher whole-body tumor SUVmean, with evidence for benefit at all SUVmean levels. ClinicalTrials.gov identifier: NCT03511664 Published under a CC BY 4.0 license. Supplemental material is available for this article.
Assuntos
Dipeptídeos , Isótopos de Gálio , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Lutécio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Compostos Radiofarmacêuticos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Lutécio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Idoso , Dipeptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Radioisótopos/uso terapêutico , Ácido Edético/análogos & derivados , Ácido Edético/uso terapêutico , Antígeno Prostático EspecíficoRESUMO
The radiohybrid (rh) concept to design targeted (and chemically identical) radiotracers for imaging or radionuclide therapy of tumors has gained momentum. For this strategy, a new bifunctional Silicon-based Fluoride Acceptor (SiFA) moiety (SiFA)SeFe was synthesized, endowed with improved hydrophilicity and high versatility of integration into rh-compounds. Preliminary radiolabeling and stability studies under different conditions were conducted using model bioconjugate peptides. Further, three somatostatin receptor 2 (sstR2)-targeted rh-compounds ((SiFA)SeFe-rhTATE1-3, TATE = (Tyr3)-octreotate) were developed. Compound (SiFA)SeFe-rhTATE3, enables labeling with 18F for PET imaging or chelation of 177Lu for therapy. The rh-compounds possess comparable receptor binding affinity and in vitro performance as good as the clinically proven gold standards. SstR2-specificity was further shown for (SiFA)SeFe-rhTATE2 using the chicken chorioallantoic membrane (CAM) model. The biodistribution of two compounds in mice showed high accumulation in tumors and excretion via the kidneys, demonstrating the clinical applicability of the (SiFA)SeFe moiety.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Receptores de Somatostatina , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Membrana Corioalantoide/metabolismo , Fluoretos/química , Radioisótopos de Flúor/química , Lutécio/química , Peptídeos/química , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Receptores de Somatostatina/metabolismo , Silício/química , Distribuição Tecidual , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Compostos de Ferro/químicaRESUMO
Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of 103Pd (T1/2 = 16.991 d) which decays to 103mRh (T1/2 = 56.12 min) then to stable 103Rh with emission of Auger and conversion electrons. Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-µm diameter; 10-µm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from 103Pd, 177Lu and 161Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to 103mRh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177Lu. In the 19-cell clusters, 103Pd absorbed doses also largely exceeded 177Lu. In both situations, 161Tb stood in-between 103Pd and 177Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease.
Assuntos
Paládio , Radioisótopos , Paládio/química , Paládio/uso terapêutico , Paládio/administração & dosagem , Radioisótopos/uso terapêutico , Radioisótopos/farmacocinética , Humanos , Lutécio/uso terapêutico , Método de Monte Carlo , Neoplasias/radioterapiaRESUMO
Prostate cancer is one of the most common cancers and leading cause of death due to cancer across the globe. This persuaded researchers to devise innovative treatment modalities that may prove effective, safe, and demonstrate better outcomes in terms of patient morbidity and survival. The advancement in theranostics such as lutetium-177 (177Lu)-PSMA-617 radioligand therapies can target prostate cancer cells causing negligible or no damage to most of the normal tissues in patients. It has been proven to effectively improve the quality of life and progression-free survival. In this study, stage IV metastatic castration-resistant prostate cancer patients were treated with 177Lu-PSMA-617, and the therapeutic response and safety of 177Lu-PSMA-617 radioligand therapy were evaluated six months after the treatment. Additionally, molecular docking studies were also conducted to find the possible mechanism at the molecular level that causes the effectiveness of 177Lu-PSMA-617 in prostate cancer.
Assuntos
Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Lutécio , Neoplasias de Próstata Resistentes à Castração , Radioisótopos , Compostos Radiofarmacêuticos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Lutécio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Dipeptídeos/uso terapêutico , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Idoso , Simulação de Acoplamento Molecular , Antígeno Prostático Específico , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Background: Treatment of castration-resistant metastatic prostate cancer with [¹77Lu]PSMA radioligand. Case presentation: A man in his seventies with metastatic prostate cancer received castration therapy for four years, developing castration-resistant disease. PET/CT with [68Ga]PSMA-11 showed high uptake in metastatic lymph nodes. The patient received 7.4 GBq [¹77Lu]PSMA-I&T (Curium, Finland) as five treatments at five-week intervals. Five weeks after the first treatment, p-PSA dropped from 154 to 53 µg/L. Five weeks after the fifth treatment, p-PSA was 1.8 µg/L. [68Ga]PSMA-11 PET/CT showed significant reduction in the size of metastases, with the largest decreasing in diameter from 10 to 4 mm. Seven months after the fifth treatment, p-PSA increased to 14.3 µg/L, and [68Ga]PSMA-11 PET/ CT revealed additional skeletal metastases, while the lymph node metastases remained unchanged. Thus, the treatment had a good but temporary effect on the metastases. Interpretation: Treatment with [¹77Lu]PSMA radioligand resulted in a temporary regression of the metastases.
Assuntos
Radioisótopos de Gálio , Lutécio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Compostos Radiofarmacêuticos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Antígeno Prostático Específico/sangue , Lutécio/uso terapêutico , Idoso , Metástase Linfática , Dipeptídeos/uso terapêutico , Dipeptídeos/farmacocinética , Oligopeptídeos , Isótopos de GálioRESUMO
Immuno-photodynamic therapy (IPDT) has emerged as a new modality for cancer treatment. Novel photosensitizers can help achieve the promise inherent in IPDT, namely, the complete eradication of a tumor without recurrence. We report here a small molecule photosensitizer conjugate, LuCXB. This IPDT agent integrates a celecoxib (cyclooxygenase-2 inhibitor) moiety with a near-infrared absorbing lutetium texaphyrin photocatalytic core. In aqueous environments, the two components of LuCXB are self-associated through inferred donor-acceptor interactions. A consequence of this intramolecular association is that upon photoirradiation with 730 nm light, LuCXB produces superoxide radicals (O2-â¢) via a type I photodynamic pathway; this provides a first line of defense against the tumor while promoting IPDT. For in vivo therapeutic applications, we prepared a CD133-targeting, aptamer-functionalized exosome-based nanophotosensitizer (Ex-apt@LuCXB) designed to target cancer stem cells. Ex-apt@LuCXB was found to display good photosensitivity, acceptable biocompatibility, and robust tumor targetability. Under conditions of photoirradiation, Ex-apt@LuCXB acts to amplify IPDT while exerting a significant antitumor effect in both liver and breast cancer mouse models. The observed therapeutic effects are attributed to a synergistic mechanism that combines antiangiogenesis and photoinduced cancer immunotherapy.
Assuntos
Celecoxib , Lutécio , Fotoquimioterapia , Fármacos Fotossensibilizantes , Porfirinas , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Animais , Humanos , Porfirinas/química , Porfirinas/farmacologia , Camundongos , Lutécio/química , Celecoxib/química , Celecoxib/farmacologia , Imunoterapia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , FemininoRESUMO
Gas sensors based on ambipolar materials offer significant advantages in reducing the size of the analytical system and enhancing its efficiency. Here, bilayer heterojunction devices are constructed using different octafluorinated phthalocyanine complexes, with Zn and Co as metal centers, combined with a lutetium bisphthalocyanine complex (LuPc2). Stable p-type behavior is observed for the ZnF8Pc/LuPc2 device under both electron-donating (NH3) and -oxidizing (NO2 and O3) gaseous species, while the CoF8Pc/LuPc2 device exhibits n-type behavior under reducing gases and p-type behavior under oxidizing gases. The nature of majority of the charge carriers of Co-based devices varies depending on the nature of target gases, displaying an ambipolar behavior. Both heterojunction devices demonstrate stable and observable response toward all three toxic gases in the sub-ppm range. Remarkably, the Co-based device is highly sensitive toward ammonia with a limit of detection (LOD) of 200 ppb, whereas the Zn-based device demonstrates exceptional sensitivity toward oxidizing gases, with excellent LOD values of 4.9 and 0.75 ppb toward NO2 and O3, respectively, which makes it one of the most effective organic heterojunction sensors reported so far for oxidizing gases.
Assuntos
Gases , Indóis , Zinco , Indóis/química , Gases/análise , Gases/química , Zinco/química , Zinco/análise , Isoindóis , Limite de Detecção , Cobalto/química , Lutécio/química , Amônia/análise , Dióxido de Nitrogênio/análise , Dióxido de Nitrogênio/química , Compostos Organometálicos/química , Poluentes Atmosféricos/análiseRESUMO
Novel theranostic approaches using radiopharmaceuticals targeting prostate-specific membrane antigen (PSMA) have emerged for treating metastatic castration-resistant prostate cancer. The physical properties and commercial availability of 177Lu make it one of the most used radionuclides for radiopharmaceutical therapy (RPT). In this literature review, we aimed at comparing the dosimetry of the most used [177Lu]Lu-PSMA RPT compounds. Methods: This was a systematic review and metaanalysis of [177Lu]Lu-PSMA RPT (617, I&T, and J591) dosimetry in patients with prostate cancer. Absorbed doses in Gy/GBq for each organ at risk (kidney, parotid and submandibular glands, bone marrow, liver, and lacrimal glands) and for tumor lesions (bone and nonbone lesions) were extracted from included articles. These were used to estimate the pooled average absorbed dose of each agent in Gy/GBq and in Gy/cycle, normalized to the injected activity (per cycle) used in the VISION (7.4 GBq), SPLASH (6.8 GBq), and PROSTACT trials (5.8 GBq). Results: Twenty-nine published articles comprising 535 patients were included in the metaanalysis. The pooled doses (weighted average across studies) of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T were 4.04 Gy/GBq (17 studies, 297 patients) and 4.70 Gy/GBq (10 studies, 153 patients) for the kidney (P = 0.10), 5.85 Gy/GBq (14 studies, 216 patients) and 2.62 Gy/GBq (5 studies, 86 patients) for the parotids (P < 0.01), 5.15 Gy/GBq (5 studies, 81 patients) and 4.35 Gy/GBq (1 study, 18 patients) for the submandibular glands (P = 0.56), 11.03 Gy/GBq (6 studies, 121 patients) and 19.23 Gy/GBq (3 studies, 53 patients) for the lacrimal glands (P = 0.20), 0.24 Gy/GBq (12 studies, 183 patients) and 0.19 Gy/GBq (4 studies, 68 patients) for the bone marrow (P = 0.31), and 1.11 Gy/GBq (9 studies, 154 patients) and 0.56 Gy/GBq (4 studies, 56 patients) for the liver (P = 0.05), respectively. Average tumor doses tended to be higher for [177Lu]Lu-PSMA-617 than for [177Lu]Lu-PSMA-I&T in soft tissue tumor lesions (4.19 vs. 2.94 Gy/GBq; P = 0.26). Dosimetry data of [177Lu]Lu-J591 were limited to one published study of 35 patients with reported absorbed doses of 1.41, 0.32, and 2.10 Gy/GBq to the kidney, bone marrow, and liver, respectively. Conclusion: In this metaanalysis, there was no significant difference in absorbed dose between [177Lu]Lu-PSMA-I&T and [177Lu]Lu-PSMA-617. There was a possible trend toward a higher kidney dose with [177Lu]Lu-PSMA-I&T and a higher tumor lesion dose with [177Lu]Lu-PSMA-617. It remains unknown whether this finding has any clinical impact. The dosimetry methodologies were strikingly heterogeneous among studies, emphasizing the need for standardization.
Assuntos
Lutécio , Radiometria , Compostos Radiofarmacêuticos , Humanos , Masculino , Compostos Radiofarmacêuticos/uso terapêutico , Lutécio/uso terapêutico , Neoplasias da Próstata/radioterapia , Glutamato Carboxipeptidase II/metabolismo , Radioisótopos/uso terapêutico , Antígenos de Superfície/metabolismo , Antígeno Prostático EspecíficoRESUMO
Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds 1-8) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands 1-8 were successfully prepared and labeled with 68Ga or 177Lu. Among them, [68Ga]Ga-8 ([68Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [68Ga]Ga-8 revealed high tumor uptake (SUVmax: 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [177Lu]Lu-8 at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [68Ga]Ga/[177Lu]Lu-8 may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.
Assuntos
Antígenos de Superfície , Radioisótopos de Gálio , Glutamato Carboxipeptidase II , Lutécio , Neoplasias da Próstata , Masculino , Radioisótopos de Gálio/química , Animais , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Humanos , Glutamato Carboxipeptidase II/metabolismo , Camundongos , Antígenos de Superfície/metabolismo , Lutécio/química , Radioisótopos/química , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Linhagem Celular Tumoral , Distribuição Tecidual , Camundongos Nus , Hipóxia TumoralRESUMO
Introduction: Prostate Specific Membrane Antigen Positron Emission Tomography (PSMA-PET) is routinely used for the staging of patients with prostate cancer, but data on response assessment are sparse and primarily stem from metastatic castration-resistant prostate cancer (mCRPC) patients treated with PSMA radioligand therapy. Still, follow-up PSMA-PET is employed in earlier disease stages in case of clinical suspicion of disease persistence, recurrence or progression to decide if localized or systemic treatment is indicated. Therefore, the prognostic value of PSMA-PET derived tumor volumes in earlier disease stages (i.e., hormone-sensitive prostate cancer (HSPC) and non-[177Lu]Lu-PSMA-617 (LuPSMA) therapy castration resistant prostate cancer (CRPC)) are evaluated in this manuscript. Methods: A total number of 73 patients (6 primary staging, 42 HSPC, 25 CRPC) underwent two (i.e., baseline and follow-up, median interval: 379 days) whole-body [68Ga]Ga-PSMA-11 PET/CT scans between Nov 2014 and Dec 2018. Analysis was restricted to non-LuPSMA therapy patients. PSMA-PETs were retrospectively analyzed and primary tumor, lymph node-, visceral-, and bone metastases were segmented. Body weight-adjusted organ-specific and total tumor volumes (PSMAvol: sum of PET volumes of all lesions) were measured for baseline and follow-up. PSMAvol response was calculated as the absolute difference of whole-body tumor volumes. High metastatic burden (>5 metastases), RECIP 1.0 and PSMA-PET Progression Criteria (PPP) were determined. Survival data were sourced from the cancer registry. Results: The average number of tumor lesions per patient on the initial PET examination was 10.3 (SD 28.4). At baseline, PSMAvol was strongly associated with OS (HR 3.92, p <0.001; n = 73). Likewise, response in PSMAvol was significantly associated with OS (HR 10.48, p < 0.005; n = 73). PPP achieved significance as well (HR 2.19, p <0.05, n = 73). Patients with hormone sensitive disease and poor PSMAvol response (upper quartile of PSMAvol change) in follow-up had shorter outcome (p < 0.05; n = 42). PSMAvol in bones was the most relevant parameter for OS prognostication at baseline and for response assessment (HR 31.11 p < 0.001; HR 32.27, p < 0.001; n = 73). Conclusion: PPP and response in PSMAvol were significantly associated with OS in the present heterogeneous cohort. Bone tumor volume was the relevant miTNM region for OS prognostication. Future prospective evaluation of the performance of organ specific PSMAvol in more homogeneous cohorts seems warranted.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/patologia , Pessoa de Meia-Idade , Seguimentos , Radioisótopos de Gálio , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Glutamato Carboxipeptidase II/metabolismo , Compostos Radiofarmacêuticos , Antígenos de Superfície/metabolismo , Isótopos de Gálio , Prognóstico , Lutécio/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Carga Tumoral , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Dipeptídeos/uso terapêuticoRESUMO
Background: Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [177Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC. Methods: In this study, we evaluated the therapeutic and immunological action of [177Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [177Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [177Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling. Results: Biodistribution studies showed high tumor uptake of [177Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [177Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [177Lu]Lu-DOTA-hG250 + a-PD1. Ex vivo analyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment. Conclusions: Subtherapeutic [177Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.
Assuntos
Anidrase Carbônica IX , Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/patologia , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Renais/radioterapia , Anidrase Carbônica IX/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Humanos , Linhagem Celular Tumoral , Radioisótopos/uso terapêutico , Radioisótopos/farmacologia , Radioisótopos/administração & dosagem , Lutécio/uso terapêutico , Feminino , Antígenos de Neoplasias/metabolismo , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Proteína Tumoral 1 Controlada por Tradução , Ensaios Antitumorais Modelo de Xenoenxerto , Terapia Combinada/métodos , Camundongos Endogâmicos BALB C , Anticorpos MonoclonaisRESUMO
Background: 177Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy. Methods: Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT. Results: Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year (p < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level (p < 0.05) for patients with progressive disease. Conclusion: We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.
Assuntos
Neoplasias Intestinais , MicroRNAs , Tumores Neuroendócrinos , RNA Mensageiro , Humanos , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/radioterapia , Tumores Neuroendócrinos/patologia , Masculino , Feminino , MicroRNAs/sangue , MicroRNAs/genética , Pessoa de Meia-Idade , Neoplasias Intestinais/sangue , Neoplasias Intestinais/patologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/tratamento farmacológico , RNA Mensageiro/genética , RNA Mensageiro/sangue , Idoso , Seguimentos , Adulto , Prognóstico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Receptores de Peptídeos/genética , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/administração & dosagem , Lutécio , RadioisótoposRESUMO
PURPOSE: Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS: Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS: Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION: CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.
Assuntos
Hematopoiese Clonal , Lutécio , Tumores Neuroendócrinos , Trombocitopenia , Humanos , Masculino , Feminino , Idoso , Trombocitopenia/genética , Trombocitopenia/etiologia , Tumores Neuroendócrinos/genética , Estudos Prospectivos , Pessoa de Meia-Idade , Lutécio/uso terapêutico , Lutécio/efeitos adversos , Hematopoiese Clonal/genética , Idoso de 80 Anos ou mais , Adulto , Radioisótopos/uso terapêutico , Radioisótopos/efeitos adversosRESUMO
The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of 177Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSHhex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2}, DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex, DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex, and DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first. Then the biodistribution of 177Lu-labeled peptides was determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to choose the lead peptide for further examination. The full biodistribution and melanoma imaging properties of 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex were further evaluated using B16/F10 melanoma-bearing C57 mice. DOTA-Lys(IBU)-GG-Nle-CycMSHhex, DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex, DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex, and DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex displayed the IC50 values of 1.41 ± 0.37, 1.52 ± 0.08, 0.03 ± 0.01, and 0.58 ± 0.06 nM on B16/F10 melanoma cells, respectively. 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex exhibited the lowest liver and kidney uptake among all four designed 177Lu peptides. Therefore, 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex was further evaluated for its full biodistribution and melanoma imaging properties. The B16/F10 melanoma uptake of 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex was 19.5 ± 3.12, 24.12 ± 3.35, 23.85 ± 2.08, and 10.80 ± 2.89% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Moreover, 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex could clearly visualize the B16/F10 melanoma lesions at 2 h postinjection. The conjugation of IBU with or without a linker to GGNle-CycMSHhex affected the MC1R binding affinities of the designed peptides. The charge of the linker played a key role in the liver and kidney uptake of 177Lu-Asp-IBU, 177Lu-Asn-IBU, and 177Lu-Dab-IBU. 177Lu-Asp-IBU exhibited higher tumor/liver and tumor/kidney uptake ratios than those of 177Lu-Asn-IBU and 177Lu-Dab-IBU, underscoring its potential evaluation for melanoma therapy in the future.
Assuntos
Ibuprofeno , Lutécio , alfa-MSH , Animais , Camundongos , alfa-MSH/química , alfa-MSH/farmacocinética , Lutécio/química , Distribuição Tecidual , Ibuprofeno/química , Ibuprofeno/farmacocinética , Ibuprofeno/farmacologia , Linhagem Celular Tumoral , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Radioisótopos/química , Melanoma/metabolismo , Melanoma/tratamento farmacológico , Albuminas/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , FemininoAssuntos
Neoplasias das Glândulas Suprarrenais , Lutécio , Compostos Radiofarmacêuticos , Idoso , Humanos , Masculino , Neoplasias das Glândulas Suprarrenais/secundário , Neoplasias das Glândulas Suprarrenais/radioterapia , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/uso terapêutico , Antígeno Prostático Específico , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
BACKGROUND: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. METHODS: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. RESULTS: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. CONCLUSIONS: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.
Assuntos
Endopeptidases , Radioisótopos de Gálio , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Lutécio/química , Humanos , Animais , Camundongos , Distribuição Tecidual , Radioisótopos/química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Radioisótopos de Gálio/química , Linhagem Celular Tumoral , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Gelatinases/antagonistas & inibidores , Gelatinases/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Feminino , Masculino , Nanomedicina TeranósticaRESUMO
Internal dosimetry supports safe and effective patient management during radionuclide therapy. Yet, it is associated with high clinical workload, costs, and patient burden, as patient scans at multiple time points (MTPs) must be acquired. Dosimetry based on imaging at a single time point (STP) has continuously gained popularity. However, MTP protocols, used as a reference to judge the validity of STP dosimetry, differ depending on local requirements and deviate from the unknown patient-specific ground truth pharmacokinetics. The aim of this study was to compare the error and optimum time point for different STP approaches using different reference MTP protocols. Methods: Whole-body SPECT/CT scans of 7 patients (7.4-8.9 GBq of [177Lu]Lu-PSMA-I&T) were scheduled at 24, 48, 72, and 168 h after injection. Sixty lesions, 14 kidneys, and 10 submandibular glands were delineated in the SPECT/CT data. Two curve models, that is, a mono- and a biexponential model, were fitted to the MTP data, in accordance with goodness-of-fit analysis (coefficients of variation, sum of squared errors). Three population-based STP approaches were compared: one method published by Hänscheid et al., one by Jackson et al., and one using population-based effective half-lives in the mono- or biexponential curve models. Percentage differences between STP and MTP dosimetry were evaluated. Results: Goodness-of-fit parameters show that a monoexponential function and a biexponential function with shared population-based parameters and physical tail are reasonable reference models. When comparing both reference models, we observed maximum differences of -44%, -19%, and -28% in the estimated absorbed doses for lesions, kidneys, and salivary glands, respectively. STP dosimetry with an average deviation of less than 10% from MTP dosimetry may be feasible; however, this deviation and the optimum imaging time point showed a dependence on the chosen reference protocol. Conclusion: STP dosimetry for [177Lu]Lu-PSMA therapy is promising to boost the integration of dosimetry into clinical routine. According to our patient cohort, 48 h after injection may be regarded as a compromise for STP dosimetry for lesions and at-risk organs. The results from this analysis show that a common gold standard for dosimetry is desirable to allow for reliable and comparable STP dosimetry.
Assuntos
Lutécio , Radiometria , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Fatores de Tempo , Dipeptídeos/uso terapêutico , Reprodutibilidade dos Testes , Masculino , Radioisótopos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Feminino , Antígeno Prostático EspecíficoRESUMO
Because of upregulated expression on cancer-associated fibroblasts, fibroblast activation protein (FAP) has emerged as an attractive biomarker for the imaging and therapy of solid tumors. Although many FAP ligands have already been developed for radiopharmaceutical therapies (RPTs), most suffer from inadequate tumor uptake, insufficient tumor residence times, or off-target accumulation in healthy tissues, suggesting a need for further improvements. Methods: A new FAP-targeted RPT with a novel ligand (FAP8-PEG3-IP-DOTA) was designed by combining the desirable features of several previous ligand-targeted RPTs. Uptake and retention of [111In]In or [177Lu]Lu-FAP8-PEG3-IP-DOTA were assessed in KB, HT29, MDA-MB-231, and 4T1 murine tumor models by radioimaging or ex vivo biodistribution analyses. Radiotherapeutic potencies and gross toxicities were also investigated by monitoring tumor growth, body weight, and tissue damage in tumor-bearing mice. Results: FAP8-PEG3-IP-DOTA exhibited high affinity (half-maximal inhibitory concentration, 1.6 nM) and good selectivity for FAP relative to its closest homologs, prolyl oligopeptidase (half-maximal inhibitory concentration, â¼14.0 nM) and dipeptidyl peptidase-IV (half-maximal inhibitory concentration, â¼860 nM). SPECT/CT scans exhibited high retention in 2 different solid tumor models and minimal uptake in healthy tissues. Quantitative biodistribution analyses revealed tumor-to-healthy-tissue ratios of more than 5 times for all major organs, and live animal studies demonstrated 65%-93% suppression of tumor growth in all 4 models tested, with minimal or no evidence of systemic toxicity. Conclusion: We conclude that [177Lu]Lu-FAP8-PEG3-IP-DOTA constitutes a promising and safe RPT candidate for FAPα-targeted radionuclide therapy of solid tumors.
Assuntos
Endopeptidases , Gelatinases , Proteínas de Membrana , Compostos Radiofarmacêuticos , Serina Endopeptidases , Animais , Camundongos , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/farmacocinética , Gelatinases/metabolismo , Humanos , Linhagem Celular Tumoral , Serina Endopeptidases/metabolismo , Proteínas de Membrana/metabolismo , Distribuição Tecidual , Feminino , Desenho de Fármacos , Lutécio/uso terapêutico , Neoplasias/radioterapia , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Terapia de Alvo Molecular , RadioisótoposRESUMO
ABSTRACT: The flare phenomenon is a transient increase in the number or intensity of lesions on bone scans after treatment, signifying curative effect. DOTA-ibandronic acid (DOTA-IBA) is a new prodrug that targets bone metastases and can be labeled with 177 Lu. Here, we report the case of a 58-year-old woman with bone metastasis, in whom the flare phenomenon was observed after 4 cycles of 177 Lu-DOTA-IBA treatment. No adverse effects were observed during the treatment and follow-up periods.