Targeted radionuclide therapy for patients with CNS metastasis: overlooked potential?

Targeted radionuclide therapy is an emerging therapeutic concept for metastatic cancer that can be considered if a tumor can be delineated by nuclear medicine imaging and also targeted based on expression of a particular target (thera-nostics). This mode of treatment can also compete with or supplement conventional radiotherapy e.g., if MRI does not fully capture the extent of disease, including microscopic metastases. Targeted radionuclide therapy for patients with thyroid cancer, with certain somatostatin receptor 2-expressing tumors and with prostate-specific membrane antigen (PSMA)-expressing prostate cancer are approved, and numerous approaches of targeted radionuclide therapy for patients with metastatic cancer are in development (e.g. using fibroblast activation protein (FAP) as a target). Although brain metastases are rare in the cancers with approved targeted radionuclide therapies, there is no a priori reason to assume that such treatments would not be effective against brain metastases if the targets are expressed and not shielded by the blood brain barrier. Here, we discuss the current state of the art and opportunities of targeted radionuclide therapies for patients with brain and leptomeningeal metastases.

Impact of TP53 loss-of-function alterations on the response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer patients.

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53-mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P<0.001), a lower median PSA change (-55% vs. -75%, P=0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P=0.003) compared to TP53-wildtype patients. Pathogenic alterations in AR, MYC, BRCA1, or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53-status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival (P<0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC.

Searching for Protein Off-Targets of Prostate-Specific Membrane Antigen-Targeting Radioligands in the Salivary Glands.

Background: Prostate specific membrane antigen (PSMA)-targeted radioligand therapies represent a highly effective treatment for metastatic prostate cancer. However, high and sustain uptake of PSMA-ligands in the salivary glands led to dose limiting dry mouth (xerostomia), especially with α-emitters. The expression of PSMA and histologic analysis couldn't directly explain the toxicity, suggesting a potential off-target mediator for uptake. In this study, we set out to search for possible off-target non-PSMA protein(s) in the salivary glands. Methods: A machine-learning based quantitative structure activity relationship (QSAR) model was built for seeking the possible off-target(s). The resulting target candidates from the model prediction were subjected to further analysis for salivary protein expression and structural homology at key regions required for PSMA-ligand binding. Furthermore, cellular binding assays were performed utilizing multiple cell lines with high expression of the candidate proteins and low expression of PSMA. Finally, PSMA knockout (PSMA-/-) mice were scanned by small animal PET/MR using [68Ga]Ga-PSMA-11 for in-vivo validation. Results: The screening of the trained QSAR model did not yield a solid off-target protein, which was corroborated in part by cellular binding assays. Imaging using PSMA-/- mice further demonstrated markedly reduced PSMA-radioligand uptake in the salivary glands. Conclusion: Uptake of the PSMA-targeted radioligands in the salivary glands remains primarily PSMA-mediated. Further investigations are needed to illustrate a seemingly different process of uptake and retention in the salivary glands than that in prostate cancer.

Angiogenic biomarkers of response to treatment with peptide receptor radionuclide therapy in neuroendocrine tumours.

BACKGROUND: Neuroendocrine tumours (NETs) are a heterogeneous group of tumours, which is characterized by rich vascularization. The role of angiogenesis in NETs has been widely researched. Peptide receptor radionuclide therapy (PRRT) is an effective treatment method for patients with disease progression in NETs. Due to the heterogeneousness of NETs, the response to treatment varies. Currently, the finding of efficient markers helpful in assessing the response to treatment in NETs is crucial. The aim of this study was to assess chromogranin A (CgA) and angiogenic factors in gastro-entero-pancreatic (GEP) and broncho-pulmonary (BP) NET patients treated with PRRT. MATERIAL AND METHODS: The study group included 40 patients with GEP NETs and BP NETs who completed four cycles of PRRT. Serum levels of CgA and angiogenic factors such as vascular endothelial growth factor (VEGF), its receptors (VEGF-R1, VEGF-R2, VEGF-R3), were assessed before and after four cycles of PRRT. All tests were determined using ELISA. RESULTS: The concentration of CgA, VEGF-R1 and VEGF-R2 decreased significantly, whereas VEGF-R3 increased significantly after PRRT. PRRT did not affect VEGF, it was similar before and after the radioisotope treatment. Based on AUROC, only for VEGF-R1 AUC was a consequence of 0.7 which can be considered as a good response to PRRT treatment. CONCLUSIONS: VEGF-R1 may be a potential biomarker useful in assessing the effectiveness of PRRT in NET patients.

Personalized dosimetry assessment of [177Lu]Lu-PSMA-617 radioligand therapy in the management of metastatic castration-resistant prostate cancer.

INTRODUCTION: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is revolutionizing the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) patients. This study aimed to establish patient-specific radiation dosimetry for [177Lu]Lu-PSMA-617 RLT in Iranian patients with mCRPC. METHOD: Twelve biopsy-proven prostate cancer patients (aged 68.73 ± 5.26 yr) underwent 6.62 ± 0.36 GBq [177Lu]Lu-PSMA-617 RLT. Post-therapy whole-body planar scans were acquired approximately at 4, 48, and 72 h post-administration, alongside a single SPECT/CT around 48 h using Siemens Symbia T2 to obtain cumulated activity. An imaging protocol and dosimetry approach were designed to balance between time efficacy and accuracy in post-therapeutic dosimetry. Using accurate activity calibration, S-values were calculated by importing SPECT/CT images as the source/geometry into the Geant4 application for the tomographic emission (GATE) Monte Carlo (MC) toolkit. The Medical Internal Radiation Dose (MIRD) scheme was followed for subsequent absorbed dose (AD) calculations in organs at risk (OAR) and tumoral lesions using the dose actor and accumulated activities for precise dose estimations. RESULTS: Using the MC approach, the mean ADs to the liver, spleen, right and left kidneys, and tumor lesions were 0.11 ± 0.04 Gy/GBq, 0.08 ± 0.03 Gy/GBq, 0.34 ± 0.09 Gy/GBq, 0.34 ± 0.10 Gy/GBq, and 0.83 ± 0.54 Gy/GBq, respectively. Notably, tumoral lesions demonstrated significantly higher ADs, indicating enhanced uptake of radiopharmaceuticals by malignant cells. CONCLUSIONS: This study indicates that the ADs of OARs and tumoral lesions from [177Lu]Lu-PSMA-617 RLT in patients with mCRPC are consistent with existing literature. The dosimetry findings suggest that increasing the administered activity of [177Lu]Lu-PSMA-617 RLT is feasible and does not pose a significant risk of adverse effects on OARs, as supported by our data. However, to validate the safety and efficacy of higher doses, further clinical follow-up studies are recommended.

Association of Declining Prostate-specific Antigen Levels with Clinical Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Receiving [177Lu]Lu-PSMA-617 in the Phase 3 VISION Trial.

BACKGROUND AND OBJECTIVE: The prognostic value of declining prostate-specific antigen (PSA) levels is under investigation in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) receiving PSMA-targeted radioligand therapy with [177Lu]Lu-PSMA-617 (177Lu-PSMA-617). This post hoc analysis of the phase 3 VISION trial aimed to evaluate associations between PSA decline and clinical and patient-reported outcomes in patients receiving 177Lu-PSMA-617. METHODS: Of 831 enrolled patients with PSMA-positive progressive mCRPC treated previously with one or more androgen receptor pathway inhibitors and one to two taxanes, 551 were randomised to 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC). Radiographic progression-free survival, overall survival, radiographic objective response rate, and patient-reported health-related quality of life (HRQoL) and pain were analysed in subgroups of patients categorised by the magnitude of unconfirmed PSA decline from baseline. KEY FINDINGS AND LIMITATIONS: Patients randomised to 177Lu-PSMA-617 with the best PSA declines of ≥0-<50% (96/551 [17%]), ≥50-<90% (152/551 [28%]), and ≥90% (83/551 [15%]) up to and including week 12 had 61%, 72%, and 88% reduced risks of radiographic disease progression or death, and 51%, 70%, and 87% reduced risks of death, respectively, versus those with increased PSA levels (160/551 [29%]), based on hazard ratios in a multivariate Cox proportional hazard model. In patients with greater PSA declines, radiographic responses were more frequent and median time to worsening in HRQoL and pain scores were longer. CONCLUSIONS AND CLINICAL IMPLICATIONS: The magnitude of PSA decline was associated with improvement in clinical and patient-reported outcomes in patients with mCRPC receiving 177Lu-PSMA-617 plus SoC in VISION. PSA decline therefore appears to have a prognostic value during 177Lu-PSMA-617 treatment in this population.

A nuclear beacon of hope: an advanced, metastatic glucagonoma treated with [177Lu]Lu-DOTA-TATE.

Glucagonoma is a rare pancreatic neuroendocrine tumor (panNET) that can be characterized by increased secretion of glucagon and distinguishing symptoms - glucagonoma syndrome with a typical dermatosis, necrolytic migratory erythema, being its most common manifestation. While surgery and somatostatin analogs remain first-line therapeutic options in panNETs, radioligand therapy with [177Lu]Lu-DOTA-TATE is a recommended second-line palliative treatment in advanced, metastatic cases. However, its prospects and efficacy are still not vastly researched in less frequent neuroendocrine neoplasms. Here, we present an extraordinary case of a metastatic glucagonoma treated with [177Lu]Lu-DOTA-TATE used as a second-line treatment in progressive disease.

Early treatment response assessment with [177Lu]PSMA whole-body-scintigraphy compared to interim PSMA-PET.

BACKGROUND: Prostate-specific membrane antigen positron emission tomography (PSMA-PET) is an essential tool for patient selection before radioligand therapy (RLT). Interim-staging with PSMA-PET during RLT allows for therapy monitoring. However, its added value over post-treatment imaging is poorly elucidated. The aim of this study was to compare early treatment response assessed by post-therapeutic whole-body scans (WBS) with interim-staging by PSMA-PET after 2 cycles in order to prognosticate OS. METHODS: Men with metastasized castration-resistant PC (mCRPC) who had received at least two cycles of RLT, and interim PSMA-PET were evaluated retrospectively. PROMISE V2 framework was used to categorize PSMA expression and assess response to treatment. Response was defined as either disease control rate (DCR) for responders or progression for non-responders. RESULTS: A total of 188 men with mCRPC who underwent RLT between February 2015 and December 2021 were included. The comparison of different imaging modalities revealed a strong and significant correlation with Cramer V test: e.g. response on WBS during second cycle compared to interim PET after two cycles of RLT (cφ = 0.888, P < 0.001, n = 188). The median follow-up time was 14.7 months (range: 3-63 months; 125 deaths occurred). Median overall survival (OS) time was 14.5 months (95% CI: 11.9-15.9). In terms of OS analysis, early progression during therapy revealed a significantly higher likelihood of death: e.g. second cycle WBS (15 vs. 25 months, P < 0.001) with a HR of 2.81 (P < 0.001) or at PET timepoint after 2 cycles of RLT (11 vs. 24 months, P < 0.001) with a HR of 3.5 (P < 0.001). For early biochemical response, a PSA decline of at least 50% after two cycles of RLT indicates a significantly lower likelihood of death (26 vs. 17 months, P < 0.001) with a HR of 0.5 (P < 0.001). CONCLUSION: Response assessment of RLT by WBS and interim PET after two cycles of RLT have high congruence and can identify patients at risk of poor outcome. This indicates that interim PET might be omitted for response assessment, but future trials corroborating these findings are warranted.

Pretherapeutic PSMA PET-Derived Semiquantitative Parameters as Predictors of PSA Response in Patients with mCRPC Receiving [ 177 Lu]Lu-PSMA-617 Radioligand Therapy.

Objective [ 177 Lu]Lu-prostate-specific membrane antigen (PSMA)-617 radioligand therapy (RLT) shows promise for metastatic castration-resistant prostate cancer (mCRPC) patients with positive PSMA positron emission tomography (PET) imaging. Identifying high-risk patients is crucial. We evaluated pretherapeutic PSMA PET-derived parameters to predict prostate-specific antigen (PSA) response in patients undergoing [ 177 Lu]Lu-PSMA-617 RLT. Materials and Methods We conducted a retrospective analysis among 27 patients (mean age: 71.0 ± 9.5 years; range: 52-85 years) who underwent PSMA PET/computed tomography (CT) and subsequent [ 177 Lu]Lu-PSMA-617 RLT between March 2019 and January 2023. After excluding patients with liver metastases, the number of patients left for analysis was 21 (14 responders and 7 nonresponders). Tumors were semiautomatically delineated with calculation of total tumor volume (PSMA-TV), lesion uptake (PSMA-TLU = PSMA-TV * standardized uptake value [SUV]mean), and lesion quotient (PSMA-TLQ = PSMA-TV/SUVmean) for each patient. Semiquantitative parameters were analyzed only in patients with mCRPC and no liver metastasis. Results In total, 17/27 patients (62.96%) had a decline in PSA levels; 15/27 patients (55.56%) experienced a decline of > 50%. Pretherapeutic PSMA PET/CT results revealed significant differences in PSMA-TV ( p = 0.003), PSMA-TLU ( p = 0.013), and PSMA-TLQ ( p = 0.011) between responders and nonresponders. SUVmax was significantly correlated to the best percentage change in PSA response after 177 Lu-PSMA-617 treatment ( r = -0.79, p = 0.006). No association was observed between PSMA-TV ( p = 0.367), PSMA-TLU ( p = 0.128), and PSMA-TLQ ( p = 0.556), with the best percentage change in PSA response after 177 Lu-PSMA-617 therapy. Conclusion Pretherapeutic PSMA PET-derived PSMA-TV, PSMA-TLU, and PSMA-TLQ were significant negative predictors of PSA response in patients with mCRPC and no liver metastasis receiving [ 177 Lu]Lu-PSMA-617 RLT.

Development of fibroblast activation protein-α radiopharmaceuticals: Recent advances and perspectives.

Fibroblast activation protein-α (FAP) has emerged as a promising target in the field of radiopharmaceuticals due to its selective expression in cancer-associated fibroblasts (CAFs) and other pathological conditions involving fibrosis and inflammation. Recent advancements have focused on developing FAP-specific radioligands for diagnostic imaging and targeted radionuclide therapy. This perspective summarized the latest progress in FAP radiopharmaceutical development, highlighting novel radioligands, preclinical evaluations, and potential clinical applications. Additionally, we analyzed the advantages and existing problems of targeted FAP radiopharmaceuticals, and discussed the key breakthrough directions of this target, so as to improve the development and conversion of FAP-targeted radiopharmaceuticals.

Therapeutic response and safety of radioligand therapy with 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer patients.

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.

Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, 223RaCl2, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225Ac-PSMA in the second-line of prostate cancer management. The future potential of 225Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols.

Analysis of Molecular Imaging and Laboratory Baseline Biomarkers in PSMA-RLT: Whole-Body Total Lesion PSMA (TLP) Predicts Overall Survival.

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [68Ga]Ga-PSMA-11 PET/CT data of n = 102 mCRPC patients receiving [177Lu]Lu-PSMA-617 RLT within a prospective registry (REALITY Study, NCT04833517) were analyzed including laboratory parameters such as alkaline phosphatase (ALP), prostate-specific antigen (PSA), gamma glutamyl transferase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), neuron specific enolase (NSE), hemoglobin (Hb), and imaging parameters such as maximum standardized uptake value of the tumor lesions (SUVmax), the mean standardized uptake value of all tumor lesions (SUVmean), the whole-body molecular tumor volume (MTV), and the whole-body total lesion PSMA (TLP). Mann-Whitney U test, univariate and multivariable Cox-regression were performed to test for association of the parameters with response and OS. The SUVmean of all lesions was significantly different between responders and non-responders (SUVmean responders 8.95 ± 2.83 vs. non-responders 7.88 ± 4.46, p = 0.003), whereas all other tested biochemical and imaging parameters did not reveal significant differences. Hb and the molecular imaging parameters MTV and TLP showed a significant association with OS (p = 0.013, p = 0.005; p = 0.009) in univariant Cox regression; however, only TLP remained significant in multivariable analysis (Hazard ratio 1.033, p = 0.009). This study demonstrates a statistically significant association between the quantitative PET/CT imaging parameter SUVmean and PSA response, as well as between the baseline TLP and OS of mCRPC patients undergoing RLT.

Investigating Combination Therapy: The Role of Lutetium-177 PSMA-617 Radioligand Therapy and Androgen Receptor Pathway Inhibitors in Metastatic Castration-Resistant Prostate Cancer.

Background: The combination of Lutetium-177 (Lu-177) PSMA-617 radioligand therapy (RLT) with androgen receptor pathway inhibitors (ARPIs) has shown promise in metastatic castration-resistant prostate cancer (mCRPC). However, real-world data on the efficacy and safety of this combination are limited. This study aimed to evaluate the impact of combination therapy with Lu-177 PSMA-617 RLT and ARPIs on progression-free survival (PFS) and overall survival (OS) in patients with mCRPC. Methods: In this retrospective study, 104 mCRPC patients receiving Lu-177 PSMA-617 RLT at our institution between December 2017 and January 2024 were divided into the following two groups those receiving Lu-177 PSMA-617 RLT plus ARPI (n = 34) and those receiving Lu-177 PSMA-617 RLT alone (n = 70). Patients received 150 to 200 millicuries Lu-177 PSMA-617 RLT in each cycle. PFS and zOS were assessed using Kaplan-Meier analysis and Cox proportional hazard models. Results: The combination therapy significantly prolonged median PFS compared to Lu-177 PSMA-617 RLT alone (11 vs. 5.6 months; HR, 0.47; 95% CI, 0.28-0.79; p < 0.01). A trend towards improved OS was also observed in the combination group (20.3 vs. 15.9 months; HR, 0.58; 95% CI, 0.33-1.02; p = 0.06). Age was a significant predictor of OS (21.2 vs. 12.4 months for younger vs. older patients; p < 0.01), while Gleason score and visceral involvement did not significantly impact PFS. The safety profile indicated that adverse effects were generally comparable between the two groups, with no statistically significant differences in the incidence of anemia, neutropenia, thrombocytopenia, nephrotoxicity, or hepatotoxicity. Conclusions: This study provides evidence that combining Lu-177 PSMA-617 RLT with ARPIs may significantly improve PFS in mCRPC patients. The potential OS benefit warrants further investigation in larger prospective trials. Age should be considered when making treatment decisions for mCRPC patients.

Combining [177Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer.

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.

Radioligand Therapy in Lymphoma: Past, Present, and Future.

In the1980s, radiolabeled cells helped understand the pathology of hemato-oncology. In the 1990s, preclinical trials evaluated radiolabeled immunotherapy with monoclonal antibodies (MoAbs) such as anti-CD20 agents labeled with Iodine-131 (Bexxar) or Yttrium-90 (Zevalin). Due to the safe and durable responses of radiolabeled MoAbs, the Food and Drug Administration approved these agents in the 2000s. Despite radioimmunotherapy's long journey, its application has recently decreased. This review will discuss the historical timeline of radioimmunotherapy, debate on advantages and difficulties, and explore trials. We will examine future directions of radioligand therapy in hemato-oncology, considering emerging molecules that may become the next theragnostic trend.

PSMA-based therapeutics for prostate cancer.

INTRODUCTION: The prostate cancer (PCa) consists the most frequently diagnosed malignancy of urogenital system in males. Traditionally, treatment of localized PCa was based on surgery or radiotherapy while hormonotherapy was used in more advanced stages. However, the implementation of radiolabels has revolutionized the landscape of prostate cancer. Specifically, prostate-specific membrane antigen (PSMA) has been investigated in different aspects of PCa therapeutic era. AREAS COVERED: A literature review is presented about the implications of PSMA radiolabels on prostate cancer treatment. PSMA tracers were initially used as an imaging technique. Afterwards, PSMA labeled with isotopes presenting cytotoxic abilities, such as lutetium-117 and actinium-225, while reports exist about the use of radioligand immunotherapy. Meanwhile, ongoing trials examine the development of novel radionuclides as well as the evolution of the PSMA-targeted ligands. EXPERT OPINION: Currently, PSMA radioligand treatment of prostate cancer is approved in the metastatic stage of the disease. Meanwhile, a variety of trials exist about its possible role in less advanced stages. However, plenty of parameters should be addressed before these implementations, such as PSMA dosage, dosimetry issues, and its safety profile. A future well-designed study with proper patient selection is mandatory to further explore PSMA radioligand theranostics perspectives.

Organ and tumor dosimetry including method simplification for [177Lu]Lu-PSMA-I&T for treatment of metastatic castration resistant prostate cancer.

BACKGROUND: Internal dosimetry in individual patients is essential for safe and effective radioligand therapy. Multiple time point imaging for accurate dosimetry is time consuming and hence can be demanding for nuclear medicine departments as well as patients. The objectives of this study were (1) to assess absorbed doses to organs at risk and tumor lesions for [177Lu]Lu-PSMA-I&T using whole body SPECT imaging and (2) to investigate possible simplified dosimetry protocols. METHODS: This study included 16 patients each treated with 4 cycles of [177Lu]Lu-PSMA-I&T. They underwent quantitative whole body SPECT/CT imaging (3 bed positions) at four time points (TP) comprising 2 h, 24 h, 48 h and 72-168 h post-injection (p.i.). Full 3D dosimetry (reference method) was performed for all patients and dose cycles for organs at risk (kidneys, parotid glands and submandibular glands) and up to ten tumor lesions per patient (resulting in 90 lesions overall). The simplified dosimetry methods (SM) included (1) generating time activity curves for subsequent cycles using a single TP of imaging applying the kinetics of dose cycle 1, and for organs at risk also (2) simple extrapolation from dose cycle 1 and (3) from both, dose cycle 1 and 2. RESULTS: Normalized absorbed doses were 0.71 ± 0.32 mGy/MBq, 0.28 ± 0.12 mGy/MBq and 0.22 ± 0.08 mGy/MBq for kidneys, parotid glands and submandibular glands, respectively. Tumor doses decreased from 3.86 ± 3.38 mGy/MBq in dose cycle 1 to 2.01 ± 2.65 mGy/MBq in dose cycle 4. Compared to the full dosimetry approach the SM 1 using single TP imaging at 48 h p.i. resulted in the most accurate and precise results for the organs at risk in terms of absorbed doses per cycle and total cumulated dose. For tumor lesions better results were achieved using the fourth TP (≥ 72 h p.i.). CONCLUSION: Simplification of safety dosimetry protocols is possible for [177Lu]Lu-PSMA-I&T therapy. If tumor dosimetry is of interest a later imaging TP (≥ 72 h p.i.) should be used/added to account for the slower kinetics of tumors compared to organs at risk.

Efficacy and safety of rechallenge [177Lu]Lu-PSMA-617 RLT after initial partial remission in patients with mCRPC: evaluation of a prospective registry (REALITY study).

AIM: Rechallenge of [177Lu]Lu-PSMA-617 radioligand therapy (RLT) was proposed for patients who initially responded to PSMA-RLT experiencing partial remission, but relapsed into progression after a certain period of remission. However, only limited data is available regarding this approach. In this study, we analyzed the efficacy and safety profile of one or more series of [177Lu]Lu-PSMA-617 RLT rechallenge in patients from a prospective registry (REALITY Study, NCT04833517) after they initially benefited from PSMA-RLT. METHODS: Forty-seven patients with metastatic castration-resistant prostate cancer (mCRPC) who had biochemical response to initial [177Lu]Lu-PSMA-617 RLT followed by disease progression received at least one (up to three) series of [177Lu]Lu-PSMA-617 RLT rechallenge. Biochemical response rates based on prostate-specific antigen (PSA) serum value, PSA-based progression-free survival (PFS) and overall survival (OS) were calculated. Adverse events of the treatment were assessed according to 'common terminology criteria for adverse events' (CTCAE). RESULTS: After one series of RLT rechallenge, a PSA decline of at least 50% was achieved in 27/47 patients (57.4%). The median PFS of all patients was 8.7 mo and the median OS was 22.7 mo, each calculated from the administration of the first rechallenge series. Patients who responded (PSA decline > 50%) to the rechallenge showed a median OS of 27.3 mo. Regarding PFS, a significant correlation (r = 0.4128, p = 0.0323) was found for these patients comparing initial and rechallenge RLT. Ten patients received a second and 3 patients received a third rechallenge series with 8/10 and 3/3 patients responding to repeated RLT rechallenge. No severe deterioration of adverse events rated by CTCAE criteria was observed. CONCLUSION: [177Lu]Lu-PSMA-617 RLT rechallenge is associated with significant PSA response and encouraging survival outcome as well as a very favourable safety profile and should therefore be considered as a straight-forward treatment option in mCRPC patients, who previously benefited from PSMA-RLT.

Comparison of 18F-DCFPyL and 68Ga-PSMA-11 for 177Lu-PSMA-617 therapy patient selection.

Purpose: 68Ga-PSMA-11 is recommended for the selection of patients for treatment in the package insert for 177Lu-PSMA-617. We aimed to compare imaging properties and post-treatment outcomes from radioligand therapy (RLT) of patients selected with 68Ga-PSMA-11 and 18F-DCFPyL. Methods: We retrospectively evaluated 80 patients undergoing PSMA RLT, who had pretreatment imaging using either 68Ga-PSMA-11 or 18F-DCFPyL. For both groups, we compared the biodistribution and lesion uptake and the PSA response to treatment. Results: Both agents had comparable biodistribution. Patients initially imaged with 18F-DCFPyL had a higher PSA response (66% vs. 42%), and more patients had a PSA50 response (72% vs. 43%) compared to patients imaged with 68Ga-PSMA-11. Conclusion: 18F-DCFPyL and 68Ga-PSMA-11 had comparable biodistribution and lesion uptake. Patients imaged with 18F-DCFPyL demonstrated clinical benefit to PSMA RLT comparable to those imaged with 68Ga-PSMA-11, and either agent can be used for screening patients.