Targeted Radionuclide Therapy Research Articles

CdTe XG-Cam: A new high-resolution x-ray and gamma-ray camera for studies of the pharmacokinetics of radiopharmaceuticals in small animals.

The recent emergence of targeted radionuclide therapy has increased the demand for imagers capable of visualizing pharmacokinetics in developing radiopharmaceuticals in the preclinical phase. Some radionuclides emit hard x-rays and gamma-rays below 100 keV, in which energy range the performance of conventional NaI scintillators is poor. Multipinhole collimators are also used for small animal imaging with a good spatial resolution but have a limited field of view (FOV). In this study, a new imager with high sensitivity over a wide FOV in the low-energy band ( 100 keV) was developed for the pharmacokineticstudy. We developed an x-ray and gamma-ray camera for high-resolution spectroscopy, named "CdTe XG-Cam," equipped with a cadmium telluride semiconductor detector and a parallel-hole collimator using a metal 3D printer. To evaluate the camera-system performance, phantom measurements with single and dual nuclides ( , , and were performed. The performance for in vivo imaging was evaluated using tumor-bearing mice to which a nuclide ( or administered. We simultaneously obtained information on and , which emit emission lines in the low-energy band with peak energies close to each other (23-26 keV for and 27-31 keV for , and applied an analytical method based on spectral model fitting to determine the individual radioactivities accurately. In the small animal imaging, the distributions of the nuclide in tumors were accurately quantified and time-activity curves in tumors areobtained. The demonstrated capability of our system to perform in vivo imaging suggests that the camera can be used for applications of pharmacokineticsresearch.

Preclinical efficacy of a PSMA-targeted actinium-225 conjugate (225Ac-macropa-pelgifatamab) - a targeted alpha therapy for prostate cancer.

Initially, prostate cancer responds to hormone therapy but eventually resistance develops. Beta emitter-based PSMA (prostate-specific membrane antigen)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs. The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide. Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi) (all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models. These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase 1 study has been initiated (NCT06052306).

Myeloid-derived suppressor cells attenuate the antitumor efficacy of radiopharmaceutical therapy using 90Y-NM600 in combination with androgen deprivation therapy in murine prostate tumors

RationaleAndrogen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer,...

Abstract 480: Nanotherapeutic strategies to improve targeted radionuclide therapy

Abstract Cancer is a leading cause of death worldwide. Several multidisciplinary approaches exist for cancer treatment, including radiotherapy and chemotherapy. Radiotherapy uses high-energy radiation to kill cancer cells; chemotherapy inhibits cancer cell proliferation and often kills cells by targeting the cell cycle. Resistance to radiotherapy and chemotherapy is a key determining factor in the outcome of therapeutic efficacy. Conventional nontargeted radiotherapy also affects distant nonirradiated cells, leading to DNA damage and changes in the cell cycle that are often linked to secondary carcinogenesis in patients. In recent years, targeted radionuclide therapy (TRT) has emerged as a promising personalized treatment strategy that delivers cytotoxic levels of radiation directly and specifically to cancer cells. Among radioisotopes,225Ac exhibits desirable properties for TRT: multiple α-particle emission and high cytotoxicity. One of the challenges with 225Ac is the nonspecific toxicity caused by the release and relocation of its decay daughters. Different approaches have been proposed to prevent the relocation of decay daughters, including nanoparticles. Nanoparticles have been pursued as a promising delivery vehicle of α-emitting radioisotopes to the tumor site. Here, we show specific targeting of Her2-positive breast cancer cells with 225Ac-radiolabeled lanthanum orthovanadate (LaVO4) nanoparticles. Nanoparticles’ surfaces were functionalized to improve biocompatibility and conjugated to target cancer cells, respectively. Cellular uptake and localization of these engineered nanoparticles were analyzed by a Confocal microscope and IncuCyte live cell analysis system. Results confirm its localization in the nucleus following the endolysosomal path, enhancing the nanoparticles’ effectiveness as a delivery vehicle for α-emitting radioisotopes with the potential of increased treatment efficacy. Upon addition of cancer-targeting ligands, these nanoparticles can achieve higher efficiency by delivering the radioisotope to the tumor cells with a potential of safe encapsulation of all α-emitters in the decay chain. The anticancer efficiency of 225Ac-radiolabeled nanoparticles was demonstrated by a dose-dependent effective killing of 3D breast cancer spheroids using both IncuCyte live imaging and the cell survival assays. Ultimately, the results of this study will be crucial in determining the future use of targeted radiolabeled nanoparticle-based delivery systems as an approach for more efficacious cancer treatment. Citation Format: Debjani Pal, Miguel Toro Gonzáleza, Amber N. Bibleb, Brian Sanders, Anna Plechaty, Owee Kirpekar, Mircea Podar, Sandra M. Davern. Nanotherapeutic strategies to improve targeted radionuclide therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 480.

Abstract 702: Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds

Abstract Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Several treatment strategies are used including the FDA approved 177Lu-vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment due to tumor intrinsic resistance mechanisms. Therefore, the combination of targeted radionuclide therapy with inhibitors against e.g. DNA damage response, cell cycle progression or cell survival pathways are investigated to enhance the radiosensitivity of the tumor. Current models to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we have developed a radioresistant patient-derived xenograft (PDX) prostate cancer model (ST1273, XenoSTART), that is positive for PSMA. Resistance to radiation was initially established by sequential irradiation of the tumors with external beam radiation. Moreover, the model has proven to be resistant towards treatment with 30 MBq 177Lu-PSMA-617. Utilizing this radioresistant model we are now able to investigate the treatment response of 177Lu-PSMA-617 in combination with different drug inhibitor classes to evaluate their potential radiosensitizing effect. The PARP inhibitor, Olaparib, was administered at 50 mg/kg QDx48 alone or in combination with a single dose of 177Lu-PSMA-617 in radioresistant ST1273 tumor bearing NMRI nude mice. First results showed a prolonging treatment effect of Olaparib given in combination with 177Lu-PSMA-617 compared to 177Lu-PSMA-617 alone. Tumor relapse was observed 29 days after treatment with 177Lu-PSMA-617 alone, whereas it was observed 49 days after combination treatment. Olaparib given alone did not influence tumor growth. To further investigate the mechanism of resistance we are currently investigating the radiosensitizing potential of additional compounds and evaluating the tumors by RNA- and whole-exome- sequencing. Altogether, we successfully established a PSMA positive prostate cancer model resistant to PSMA targeted radionuclide therapy. With this model we are able to investigate the radiosensitizing effect of different drug classes. Citation Format: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen. Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 702.

Abstract 6034: PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer

Abstract Introduction: Prostate cancer continues to be a highly prevalent cancer diagnosis among men and a leading cause of cancer related deaths worldwide. With the introduction[177Lu]Lu-PSMA-617, targeted radionuclide therapy has proven successful in increasing survival time for patients with metastasized castration resistant prostate cancer. However, despite encouraging results, such patients tend to develop progressive disease, and thus, enhanced efficacy is warranted. To this end, the use of radiopharmaceuticals harnessing alpha-emitters is a promising venue due to the potent energy deposition and short range of alpha particles in tissue. Here, we employ the PSMA targeting vector, [211At]PSAt-3, for targeted alpha radionuclide therapy in a preclinical prostate cancer model. Methods: [211At]PSAt-3, a structural derivative of PSMA-617, in which the L-2-naphtylalanine was replaced by L-3-[211At]astato-phenylalanine, was obtained by electrophilic [211At]astatodesilylation. Evaluation of [211At]PSAt-3 was conducted in male inbred nude mice of Balb/c background xenografted subcutaneously with human prostate cancer cells (LNCaP). Prior biodistribution studies were carried out with approximately 100 kBq intravenous injections, and subsequent biodistribution 2, 6 and 24h post injection (P.I.). For establishment of therapeutic effect, a single intravenous dose of [211At]PSAt-3 was administered. To asses hematological toxicity, blood cell composition was assessed weekly. Results: Favorable tumor uptake of 15.2±6 %ID/g was observed 2h after injection of [211At]PSAt-3 in LNCaP xenografted nude mice, with subsequent 9±5.1% ID/g and 6.4±2.4% ID/g 6 and 24h P.I., respectively. [211At]PSAt-3 cleared mainly by the kidneys, in which uptake was 72, 38 and 6% ID/g at 2, 6 and 24h P.I., respectively. Thyroid/throat uptake remained low at ~0.1% ID for all timepoints investigated, indicating a low degree of de-astatination. Initial efficacy studies using a single intravenous dose of 0.5 MBq (~20 MBq/kg) demonstrated significant growth delay and tumor volume reduction compared with control mice (saline). Blood platelet count was reduced after administration of [211At]PSAt-3 and subsequently recovered. No signs of severe toxicity, and no significant weight loss between control and treated mice was observed, suggesting that the treatment is well tolerated. Conclusion: 0.5 MBq [211At]PSAt-3 was well tolerated in mice and demonstrated tumor volume reduction and significant delay of tumor growth. These findings suggest [211At]PSAt-3 as a promising candidate for clinical translation. Citation Format: Lars Hvass, Marius Müller, Anne Clausen, Matthias Herth, Andreas Kjaer. PSMA targeted alpha radiopharmaceutical [211At]PSAt-3 inhibits tumor growth in a preclinical model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6034.

Abstract 7374: Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma

Abstract Background: Resistance of cancer cells to monotherapies has led to the development of sequential or combination therapy regimens. However, dosing and scheduling of these therapies is challenging due to the numerous dosing and scheduling combinations that can be given. Mathematical models are thus critical tools for addressing this challenge as multiple therapy combinations can be tested in silico to finalize a patient-specific therapeutic regimen in vivo. Here we develop a mathematical framework for combining targeted radiation therapy (TRT) with Chimeric Antigen Receptor (CAR)-T cell immunotherapy and demonstrate the use of in silico techniques to schedule these therapies for maximizing survival. Methods: In the mathematical framework tumor growth is assumed to be exponential and the effect of radiation on both tumor cells and CAR-T cells is modeled using the linear-quadratic model of cell survival to radiation. A predator-prey model is used to characterize the dynamics of tumor and CAR-T cells. Using a preclinical disseminated mouse model of multiple myeloma (MM1S), we evaluate tumor response to 200 nCi of 225Ac-DOTA-Daratumumab (TRT) and 1 million cells of CS1 CAR-T cell therapy both as monotherapies as well as in combination. Tumor burden tracked using bioluminescence imaging from six groups of mice is used to calibrate model parameters: (a) No treatment. (b) Day 7 TRT. (c) Day 7 CAR-T cell therapy. (d) Day 7 TRT + Day 18 CAR-T cell therapy. (e) Day 7 TRT + Day 25 CAR-T cell therapy. (f) Day 7 TRT + Day 32 CAR-T cell therapy. Response to therapy is evaluated using progression-free survival (PFS), overall survival (OS) and time to minimum tumor burden (tmin), all of which are calculated using the predicted in silico tumor burden dynamics and the tumor burden at the start of first therapy. We evaluate these response metrics for various dosing and scheduling regimens. Results: Therapy intervals that were too short or too long are shown to be detrimental for therapeutic efficacy. TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing, while the interval being too long results in tumor regrowth, negatively impacting tumor control and survival. If a single dose is split into multiple doses, the splitting is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. Based on the model parameters we estimate the minimum required TRT activity and CAR-T cell dose to demonstrate an improvement in PFS. Conclusions: The proposed model demonstrates the impact of different dosing and scheduling regimens of TRT and CAR-T therapy on survival metrics. It is a potent tool for translating preclinical results to the clinic and eventually tailor therapy regimens for patients. Citation Format: Vikram Adhikarla, Dennis Awuah, Enrico Caserta, Megan Minnix, Maxim Kuznetsov, Amrita Krishnan, Jeffrey Y. Wong, John E. Shively, Xiuli Wang, Flavia Pichiorri, Russell C. Rockne. Mathematical modeling of targeted radionuclide therapy and CAR-T cell immunotherapy for maximizing therapeutic efficacy in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7374.

Abstract 7582: Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT)

Abstract Introduction: Predictors of outcomes after PSMA-TRT are still being established. Liver metastases (mets) have been associated with poor response. Mutations in genes encoding DNA damage repair (DDR) and TP53 affect radiosensitivity. Here we describe a cohort of patients with mCRPC and liver metastases treated on clinical trials of PSMA-TRT. Methods: 39 patients with liver mets were enrolled on phase I/II PSMA-TRT studies between Jan 2006 to Apr 2022. Patients received alpha therapy (225Ac-J591), beta therapy (fractionated 177Lu-PSMA-617, single-dose and fractionated 177Lu-J591) or a combination of both (225Ac-591 and 177Lu-PSMA-I&T). All patients included in this analysis had CT imaging; patients enrolled after 2017 had PSMA-PET imaging. 15 patients also had genomic analysis completed. Results: Median age was 69 (range 55-93), PSA 85.7 (2.45-9614). 39 (100%) bone mets, 33 (84.6%) LN, 9 (23.1%) lung. 22 (56.4%) greater than 1 ARPI, 23 (59.0%) greater thanc 1 chemo, 13 (33.3%) sip-T, 7 (17.9%) Ra-223, 4 (10.2%) prior TRT (with concurrent liver mets). Of the 19 with both CT and PSMA PET, 18 (94.7%) were identified on PSMA PET (including 8 PET only), 10 (55.6%) on CT (1 CT only, i.e. non-PSMA PET avid). Median whole body PSMA-imaging score (PSMA-IS) was 4 (range 1-4), with 7 (17.9%) 1-2 and 32 (82.1%) 3-4. 9 (23.0%) received alpha-TRT, 26 (66.7%) beta-TRT, and 4 (10.3%) combo-TRT. Somatic or germline analysis was completed in 15 (38.5%) of 39 patients. 8 (53.3%) had mutations in DNA repair pathways (3 in BRCA2, 3 in CHEK 2, 1 in FANC, 1 in MSH2). 7 (46.7%) had mutations in TP53. 31 patients (79.5%) had PSA decline, with 15 (38.5%) achieving PSA 50. 26 (66.7%) had baseline CTC measured; 19 (73.0%) had detectable CTC at baseline. Of these 19, 3 (15.8%) converted to undetectable after therapy and 2 (10.5%) converted to favorable CTC. PSA50 rate in alpha-TRT was 4 (44.4%), beta-TRT 8 (30.7%), combo-TRT 3 (75%). PSA50 in patients with PSMA-IS 1-2 was 1 (14.2%) compared to 14 (43.9%) in PSMA-IS 3-4. 3 (37.5%) of 8 patients with mutDDR achieved PSA50, compared to 3 (42.9%) with mutTP53. Conclusions: This dataset adds to the collective literature of two subgroups of patients with mCRPC receiving TRT: those with liver disease and those with mutations in DNA repair pathways. The results of this study suggest higher rates of response in patients receiving alpha therapy, either alone or in combination with beta therapy, and in patients with high radiotracer uptake on PSMA-PET, based on PSMA-imaging score of 3 or 4. Genomic alterations in DRR proteins did not have clear implications. Citation Format: Samuel Ruder, Michael Sun, Andres Ricaurte Fajardo, Jones Nauseef, Zachary Davidson, Joseph Thomas, Sandra Huicochea Castellanos, Ana Molina, Cora Sternberg, Amie Patel, Escarleth Fernandez, Sarah Yuan, Edward Fung, Vasilios Avlonitis, Elisabeth O'Dwyer, David Nanus, Joseph Osborne, Neil Bander, Scott Tagawa. Descriptive analysis of patients with mCRPC and liver metastases receiving alpha and beta PSMA targeted radionuclide therapy (PSMA-TRT) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7582.

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response.

Ionizing radiation has garnered considerable attention as a combination partner for immunotherapy due to its potential immunostimulatory effects. In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering β-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2). We hypothesized that the delivery of radiation to tumors could synergize with CAR T therapy, resulting in enhanced antitumor immunity and tumor response. To determine the optimal dosage and timing of 177Lu-DOTATATE treatment, we measured CAR T cell infiltration and expansion in tumors longitudinally through positron emission tomography (PET) using a SSTR2-specific positron-emitting radiotracer,18F-NOTA-Octreotide. In animals receiving CAR T cells and a low-dose (2.5 Gy) of TRT following the administration of 177Lu-DOTATATE, we observed a rapid regression of large subcutaneous tumors, which coincided with a dramatic increase in serum proinflammatory cytokines. Tumor burden was also reduced when a higher radiation dose (6 Gy) was delivered to the tumor. However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

Physics and small-scale dosimetry of -emitters for targeted radionuclide therapy: The case of .

Monte Carlo simulations have been considered for a long time the gold standard for dose calculations in conventional radiotherapy and are currently being applied for the same purpose in innovative radiotherapy techniques such as targeted radionuclide therapy (TRT). We present in this work a benchmarking study of the latest version of the Transport d'Ions Lourds Dans l'Aqua & Vivo (TILDA-V) Monte Carlo track structure code, highlighting its capabilities for describing the full slowing down of -particles in water and the energy deposited in cells by -emitters in the context ofTRT. We performed radiation transport simulations of -particles (10keV -100MeV ) in water with TILDA-Vand the Particle and Heavy Ion Transport code System (PHITS) version 3.33. We compared the predictions of each code in terms of track parameters (stopping power, range and radial dose profiles) and cellular S-values of the promising radionuclide astatine-211 ( ). Additional comparisons were made with available data in theliterature. The stopping power, range and radial dose profiles of -particles computed with TILDA-Vwere in excellent agreement with other calculations and available data. Overall, minor differences with PHITS were ascribed to phase effects, that is, related to the use of interaction cross sectionscomputed for water vapor or liquid water. However, important discrepancies were observed in the radial dose profiles of monoenergetic -particles, for which PHITS results showed a large underestimation of the absorbed dose compared to other codes and experimental data. The cellular S-values of computed with TILDA-V agreed within 4% with the values predicted by PHITS andMIRDcell. The validation of the TILDA-Vcode presented in this work opens the possibility to use it as an accurate simulation tool for investigating the interaction of -particles in biological media down to the nanometer scale in the context of medical research. The code may help nuclear medicine physicians in their choice of -emitters for TRT. Further research will focus on the application of TILDA-Vfor quantifying radioinduced damage on the deoxyribonucleic acid (DNA) molecule.

Nuclear medicine practice in Japan: a report of the ninth nationwide survey in 2022.

Subcommittee on Survey of Nuclear Medicine Practice in Japan has performed a nationwide survey of nuclear medicine practice every 5years since 1982 to survey contemporary nuclear medicine practice and its changes over the years. The subcommittee sent questionnaires, including the number and category of examinations as well as the kind of the radiopharmaceuticals during the 30days of June 2022 to all nuclear medicine institutes in Japan. The total numbers of them for the year 2022 were estimated depends on the 1-month data. A total of 1095 institutes responded to the survey, including 364 positron emission tomography (PET) centers. The recovery rate was 90.6%. The number of gamma cameras installed was 1299 in total, with 2.5% decrease in 5years. Dual-head cameras and hybrid SPECT/CT scanners accounted for 83.8% and 35.5%, respectively. The number of single-photon tracer studies in 2022 was 1.11million which means increase in 2.7% in 5years. Bone scintigraphy was a leading examination (31.0%), followed by myocardial scintigraphy (27.1%) and cerebral perfusion study (23.8%) in order. The percentage of SPECT studies showed an increase from 63.5% in previous survey to 66.8% in this survey. PET centers have also increased from 389 to 412, as compared with the previous one. One hundred and twenty-two PET centers have installed one or two in-house cyclotrons. Increasing trends of the PET studies were observed from 1992 to 2017, the trend changed and PET studies showed 1.5% decrease in 5years. 18F-FDG accounted for 98.6% (610,497 examinations). PET examinations using 11C-methionine, 13N-NH3 and 11C-PIB have decreased, with 1624, 2146 and 525 examinations, respectively in 2022. The total number of nuclear medicine examination was eventually increased by 1.0%. Therapies for pheochromocytoma or paraganglioma (PPGL) with 131I-MIBG and for neuroendocrine tumor with 177Lu-DOTA-TATE were newly started, however, a total number of targeted radionuclide therapy was decreased by 17.7% because 131I-radioiodine and 223Ra targeted therapies were decreased and supply of some radioisotopes was discontinued. 131I-radioiodine targeted therapy showed a decrease in 5years (- 15.9%), including 4099 patients for thyroid cancer. The number of out-patient thyroid bed ablation therapy with 1110MBq of 131I was also decreased to 1015 per year. The number of admission rooms specialized for radionuclide targeted therapy increased from 157 to 160. The number of 223Ra targeted therapies for castration-resistant metastatic prostate cancer (mCRPC) was 1041 patients. This survey was performed during COVID-19 pandemic, however, total number of nuclear medicine examinations was almost same as previous survey (+ 1.0%). Radionuclide therapies with 131I-MIBG and 177Lu-DOTA-TATE were newly started, and new radionuclide therapy will be available in future, therefore, the development of radionuclide therapy will be continued. We are convinced that this survey report is useful in understanding the current status of the nuclear medicine practice in Japan, and in devising the new strategy to strengthen a role ofnuclear medicine.

Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands.

Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake. High renal accumulation of radioactive compounds may lead to nephrotoxicity, and therefore, the kidneys are often the dose-limiting organs in TRT with these radioligands. Over the years, different strategies have been developed aiming for reduced kidney retention and enhanced therapeutic efficacy of radioligands. In this review, we will give an overview of the efforts and achievements of the used strategies, with focus on the therapeutic potential of low-to-moderate-molecular-weight molecules. Among the strategies discussed here is coadministration of compounds that compete for binding to the endocytic receptors in the proximal tubuli. In addition, the influence of altering the molecular design of radiolabeled ligands on pharmacokinetics is discussed, which includes changes in their physicochemical properties and implementation of cleavable linkers or albumin-binding moieties. Furthermore, we discuss the influence of chelator and radionuclide choice on reabsorption of radioligands by the kidneys.

Autophagy inhibition improves the targeted radionuclide therapy efficacy of 131I-FAP-2286 in pancreatic cancer xenografts

PurposesRadiotherapy can induce tumor cell autophagy, which might impair the antitumoral effect. This study aims to investigate the effect of autophagy inhibition on the targeted radionuclide therapy (TRT) efficacy of 131I-FAP-2286 in pancreatic cancer.MethodsHuman pancreatic cancer PANC-1 cells were exposed to 131I-FAP-2286 radiotherapy alone or with the autophagy inhibitor 3-MA. The autophagy level and proliferative activity of PANC-1 cells were analyzed. The pancreatic cancer xenograft-bearing nude mice were established by the co-injection of PANC-1 cells and pancreatic cancer-associated fibroblasts (CAFs), and then were randomly divided into four groups and treated with saline (control group), 3-MA, 131I-FAP-2286 and 131I-FAP-2286 + 3-MA, respectively. SPECT/CT imaging was performed to evaluate the bio-distribution of 131I-FAP-2286 in pancreatic cancer-bearing mice. The therapeutic effect of tumor was evaluated by 18F-FDG PET/CT imaging, tumor volume measurements, and the hematoxylin and eosin (H&E) staining, and immunohistochemical staining assay of tumor tissues.Results131I-FAP-2286 inhibited proliferation and increased the autophagy level of PANC-1 cells in a dose-dependent manner. 3-MA promoted 131I-FAP-2286-induced apoptosis of PANC-1 cells via suppressing autophagy. SPECT/CT imaging of pancreatic cancer xenograft-bearing nude mice showed that 131I-FAP-2286 can target the tumor effectively. According to 18F-FDG PET/CT imaging, the tumor growth curves and immunohistochemical analysis, 131I-FAP-2286 TRT was capable of suppressing the growth of pancreatic tumor accompanying with autophagy induction, but the addition of 3-MA enabled 131I-FAP-2286 to achieve a better therapeutic effect along with the autophagy inhibition. In addition, 3-MA alone did not inhibit tumor growth.Conclusions131I-FAP-2286 exposure induces the protective autophagy of pancreatic cancer cells, and the application of autophagy inhibitor is capable of enhancing the TRT therapeutic effect.

High Separation Factor, High Molar Activity, and Inexpensive Purification Method for the Production of Pure 165Er.

Introduction: Auger electron-emitting radionuclides with low (0.001-1 keV) energy, short-range (2-500 nm), and high linear energy transfer (4-26 keV/μm) can play an important role in the targeted radionuclide therapy (TRT) of cancer. 165Er is a pure Auger electron-emitting radionuclide, making it a useful tool for the fundamental studies of the biological effects of Auger electrons. This work develops a simple, inexpensive, high separation factor, and high molar activity radiochemical isolation process for the production of 165Er (t1/2 10.36 h) suitable for TRT in vitro and in vivo studies using irradiated natHo solid targets. Methods: Small medical cyclotron proton-irradiation of natHo targets produced 165Er in GBq scale quantities. 165Er was isolated using cation exchange chromatographic resin (AG 50W-X8, 200-400 mesh, 20 mL, under atmospheric pressure) using α-hydroxyisobutyric acid (70 mM, pH 4.75) followed by extraction using TK212, TK211, and TK221 extraction chromatographic columns. Radio nuclidic and chemical purity of the final 165Er were confirmed using HPGe Gamma spectrometry and induction coupled plasma-mass spectrometry analysis, respectively. The purified 165Er was radiolabeled with two radiometal chelators (DOTA and Crown) and used to produce a new Auger electron-emitting radiopharmaceutical, [165Er]Er-Crown-TATE. Results: Irradiation of 200 mg natHo targets with 20-30 μA of 12.8 MeV protons produced 165Er at 25 ± 5 MBq·μA-1·h-1. The 4.5 ± 0.5 h radiochemical isolation yielded GBq scale of 165Er in 0.05 M HCl (2 mL) with a radiochemical yield of 78.0 ± 5.6% decay corrected to the end of bombardment (EoB) and a Ho/165Er separation factor of (1.14 ± 0.25) × 106. The product showed high radio nuclidic purity and chemical purity. Concentration-dependent radiolabeling experiments with Crown and DOTA were performed resulting in the successful labeling of 165Er with high (>90%) radiochemical yield. Radiolabeling experiments with Crown-TATE were performed 8 h after EoB and synthesized [165Er]Er-Crown-TATE at molar activities of 202.4 MBq·nmol-1 at the end of synthesis (EoS). Conclusions: A 3 h cyclotron irradiation and 4.5 h radiochemical separation produced GBq-scale 165Er suitable for producing radiopharmaceuticals at molar activities satisfactory for investigations of targeted radionuclide therapeutic effects of Auger electron emissions. This will enable future fundamental radiation biology experiments of pure Auger electron-emitting therapeutic radiopharmaceuticals, such as [165Er]Er-Crown-TATE, which will be used to understand the impact of Auger electrons in TRT.

Ultrasmall Gold Nanoparticles Radiolabeled with Iodine-125 as Potential New Radiopharmaceutical.

The relatively high linear energy transfer of Auger electrons, which can cause clustered DNA damage and hence efficient cell death, makes Auger emitters excellent candidates for attacking metastasized tumors. Moreover, gammas or positrons are usually emitted along with the Auger electrons, providing the possibility of theragnostic applications. Despite the promising properties of Auger electrons, only a few radiopharmaceuticals employing Auger emitters have been developed so far. This is most likely explained by the short ranges of these electrons, requiring the delivery of the Auger emitters to crucial cell parts such as the cell nucleus. In this work, we combined the Auger emitter 125I and ultrasmall gold nanoparticles to prepare a novel radiopharmaceutical. The 125I labeled gold nanoparticles were shown to accumulate at the cell nucleus, leading to a high tumor-killing efficiency in both 2D and 3D tumor cell models. The results from this work indicate that ultrasmall nanoparticles, which passively accumulate at the cell nucleus, have the potential to be applied in targeted radionuclide therapy. Even better tumor-killing efficiency can be expected if tumor-targeting moieties are conjugated to the nanoparticles.

Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector.

161 Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p<0.001), anemia in 122 (73%) vs 26 (33%) (P<0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p<0.001). Gr >3 neutropenia occurred in 79 (47%) and Gr >3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p<0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p<0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p<0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p<0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&T, which are more commonly associated with non-hematologic toxicities.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

The Challenge of Single-Photon Emission Computed Tomography Image Segmentation in the Internal Dosimetry of 177Lu Molecular Therapies.

The aim of this article is to review the single photon emission computed tomography (SPECT) segmentation methods used in patient-specific dosimetry of 177Lu molecular therapy. Notably, 177Lu-labelled radiopharmaceuticals are currently used in molecular therapy of metastatic neuroendocrine tumours (ligands for somatostatin receptors) and metastatic prostate adenocarcinomas (PSMA ligands). The proper segmentation of the organs at risk and tumours in targeted radionuclide therapy is an important part of the optimisation process of internal patient dosimetry in this kind of therapy. Because this is the first step in dosimetry assessments, on which further dose calculations are based, it is important to know the level of uncertainty that is associated with this part of the analysis. However, the robust quantification of SPECT images, which would ensure accurate dosimetry assessments, is very hard to achieve due to the intrinsic features of this device. In this article, papers on this topic were collected and reviewed to weigh up the advantages and disadvantages of the segmentation methods used in clinical practice. Degrading factors of SPECT images were also studied to assess their impact on the quantification of 177Lu therapy images. Our review of the recent literature gives an insight into this important topic. However, based on the PubMed and IEEE databases, only a few papers investigating segmentation methods in 177Lumolecular therapy were found. Although segmentation is an important step in internal dose calculations, this subject has been relatively lightly investigated for SPECT systems. This is mostly due to the inner features of SPECT. What is more, even when studies are conducted, they usually utilise the diagnostic radionuclide 99mTc and not a therapeutic one like 177Lu, which could be of concern regarding SPECT camera performance and its overall outcome on dosimetry.

Radiomics and Artificial Intelligence in Radiotheranostics: A Review of Applications for Radioligands Targeting Somatostatin Receptors and Prostate-Specific Membrane Antigens.

Radiotheranostics refers to the pairing of radioactive imaging biomarkers with radioactive therapeutic compounds that deliver ionizing radiation. Given the introduction of very promising radiopharmaceuticals, the radiotheranostics approach is creating a novel paradigm in personalized, targeted radionuclide therapies (TRTs), also known as radiopharmaceuticals (RPTs). Radiotherapeutic pairs targeting somatostatin receptors (SSTR) and prostate-specific membrane antigens (PSMA) are increasingly being used to diagnose and treat patients with metastatic neuroendocrine tumors (NETs) and prostate cancer. In parallel, radiomics and artificial intelligence (AI), as important areas in quantitative image analysis, are paving the way for significantly enhanced workflows in diagnostic and theranostic fields, from data and image processing to clinical decision support, improving patient selection, personalized treatment strategies, response prediction, and prognostication. Furthermore, AI has the potential for tremendous effectiveness in patient dosimetry which copes with complex and time-consuming tasks in the RPT workflow. The present work provides a comprehensive overview of radiomics and AI application in radiotheranostics, focusing on pairs of SSTR- or PSMA-targeting radioligands, describing the fundamental concepts and specific imaging/treatment features. Our review includes ligands radiolabeled by 68Ga, 18F, 177Lu, 64Cu, 90Y, and 225Ac. Specifically, contributions via radiomics and AI towards improved image acquisition, reconstruction, treatment response, segmentation, restaging, lesion classification, dose prediction, and estimation as well as ongoing developments and future directions are discussed.

Characterization of a segmented printed circuit board (PCB) as a standard for absorbed dose to water from alpha-emitting radionuclides.

Our previous work introduced and evaluated a standard for surface absorbed dose rate per unit radioactivity to water from unsealed alpha-emitting radionuclides used in targeted radionuclide therapy (TRT). An overall uncertainty over 4.0% at k=1 was reported for the absorbed dose to air measurements, which was partially attributed to the rotational alignment uncertainty in the geometrical setup. A printed circuit board (PCB) with a segmented guard was constructed to align the extrapolation chamber (EC) and the source plates using a differential capacitance technique. The PCB EC aimed to enhance the repeatability of the ionization current measurements. The PCB EC was evaluated using a thin film 210Po source. The measured absorbed dose to air cavity was compared with the Monte Carlo (MC) calculations. Using the extrapolation method, the surface absorbed dose rate to water was calculated. The PCB EC was constructed with a 4.50mm diameter collector surrounded by four sectors and a guard electrode. The sectors were isolated for rotational alignment and later connected to the guard for ionization current measurements. A bridge circuit measured differential capacitance between opposing sectors, and a hexapod motion stage rotated the source substrate to minimize the differential capacitance. The EC was evaluated using a 210Po source with a 3.20mm diameter and 1.253 Ci radioactivity. MC simulations were performed to calculate the , , and correction factors. Ionization current measurements were performed for air gaps in the 0.3-0.525mm range and surface absorbed dose rate to water was calculated. Rotational offsets of up to 3.0° were found and the current repeatability was found to increase with the absorbed dose to air uncertainty calculated to be ∼2.0%. Using the capacitance method, the effective EC diameter was measured to be 4.53mm. The recombination, polarity, and electrometer corrections were reported to be within 1.00% across all measurement trials. The MC-calculated correction factors were calculated to be much larger than the recombination and polarity correction factors. The average , , and corrections were calculated to be 1.063, 0.9402, and 2.136, respectively. The MC-calculated absorbed dose to air was found to overestimate the absorbed dose by over 4.00% when compared with the measured absorbed dose to air. The surface absorbed dose rate to water was calculated to be Gy/s/Bq with an overall uncertainty of 4.07%. The constructed PCB EC was deemed suitable as an absorbed dose standard. A repeatable rotational alignment was achieved using the differential capacitance technique. The metal electrodes on the PCB made a difference of<1.00% on the backscatter correction when compared to the EC comprised of polystyrene-equivalent collector. A 20% difference in the surface absorbed dose rate to water was found between the two ECs, which is attributed to the cavity diameter differences leading to different magnitudes of dose fall-off along the lateral direction.