The Journal of Nuclear Medicine最新文献

Interleukin-13 receptor α-2 (IL13Rα2) is a cell surface receptor frequently expressed in solid malignancies, such as glioblastoma and melanoma, with limited expression in healthy tissue, rendering it an ideal target for noninvasive and specific tumor delineation. In this study, we report the development of 5 novel IL13Rα2-targeted human monoclonal antibodies (mAbs) KLG-1–5; in subsequent in vitro and in vivo studies after radiolabeling with ⁸⁹Zr, we evaluate their performance to identify a lead candidate. Methods: Five novel human anti-IL13Rα2 mAbs KLG-1–5 were developed and in vitro binding properties and target specificity assessed. In vivo ⁸⁹Zr-immuno-PET using KLG-1–5 was conducted in a subcutaneous U-87 MG glioblastoma mouse model, and a mass dose titration study was conducted with lead candidate KLG-3. Ex vivo biodistribution results were used to derive prospective dosimetry of ¹⁷⁷Lu-labeled KLG-3. Targeting with KLG-3 was also verified in an A-375 melanoma model using the optimized conditions determined in the U-87 MG xenograft model. Results: In vitro studies confirmed target specificity and pico- to low nanomolar binding affinity. Immuno-PET studies with KLG-1–5 in U-87 MG xenografts demonstrated continuously increasing tumoral uptake with maximal uptake at 144 h after tracer injection, clearance of the unbound tracer from the blood pool, and little uptake in any other normal tissues, leading to high-contrast images. KLG-3 provided the highest tumoral uptake and tumor–to–normal tissue ratios and was chosen as the lead candidate, and further dose optimization with this antibody led to tumoral uptake of 97 ± 6 maximum percent of injected dose per gram at 144 h after tracer injection. Ex vivo biodistribution-derived prospective dosimetry for ¹⁷⁷Lu-labeled KLG-3 predicted a favorable therapeutic index, encouraging the development of IL13Rα2-targeted radioimmunotherapy. Of note, KLG-3 performed similarly well in a melanoma model, emphasizing the versatility of this antibody. Conclusion: Lead candidate anti-IL13Rα2 mAb KLG-3 validated highly specific target binding in human glioblastoma and melanoma models, resulting in high-contrast PET images with minimal accumulation in off-target healthy tissues. Prospective dosimetry of its ¹⁷⁷Lu-labeled counterpart suggested therapeutic efficacy at relatively low injected activities, supporting further pursuit of KLG-3 in future translational radioimmunotherapy applications.

[¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) therapy has a favorable toxicity profile in patients with metastatic castration-resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasm (t-MN) has been described after [¹⁷⁷Lu]Lu-DOTATATE but has not, to our knowledge, yet been reported after [¹⁷⁷Lu]Lu-PSMA. This case series describes 5 patients with mCRPC who developed t-MN after [¹⁷⁷Lu]Lu-PSMA at our institution. Methods: In this single-center retrospective analysis, we reviewed all patients with mCRPC treated with [¹⁷⁷Lu]Lu-PSMA. Patients who developed biopsy-proven t-MN during or after [¹⁷⁷Lu]Lu-PSMA treatments are summarized with descriptive statistics. Results: From August 26, 2015, to December 31, 2022, 5 of 381 (1.3%) patients treated with [¹⁷⁷Lu]Lu-PSMA were subsequently diagnosed with t-MN. Their median age at cycle 1 (C1) was 78 y (range, 65–80 y). The median time from C1 to t-MN diagnosis was 33.6 mo (range, 6.0–58.8 mo). Previous treatments included docetaxel (n = 5), external-beam radiotherapy to metastases (n = 5), abiraterone (n = 4), enzalutamide (n = 3), and cabazitaxel (n = 3). On PSMA PET/CT, 4 (80%) patients had predominantly bone metastases and 1 (20%) had predominantly nodal metastases. They were treated with [¹⁷⁷Lu]Lu-PSMA-617 (n = 3) or [¹⁷⁷Lu]Lu-PSMA-I&T (n = 2). A median of 7 cycles (range, 4–12 cycles) of [¹⁷⁷Lu]Lu-PSMA was administered, with a median total cumulative activity of 49.2 GBq (range, 31.3–79.0 GBq). Prostate-specific antigen reduction of at least 50% or at least 80% from baseline was seen in 5 (100%) and 4 (80%), respectively. All had prostate-specific antigen progression preceding t-MN diagnosis. t-MN diagnosis included myelodysplastic syndrome with single-lineage dysplasia (n = 2), myelodysplastic syndrome with excess blasts 1 (n = 1), acute promyelocytic leukemia (n = 1), and acute myeloid leukemia (n = 1). At t-MN diagnosis, all patients presented with at least grade 2 cytopenia, involving one or more blood cell lines. Marrow genetic analysis revealed unfavorable karyotypes or mutations in all patients. Most patients received supportive care after t-MN diagnosis. Survival was 8.1, 31.3, 43.0, 56.0, and 60.4 mo from C1 and 1.8, 2.1, 6.8, 10.3, and 12.4 mo from t-MN diagnosis. Conclusion: In the mCRPC population after chemotherapy, we describe a low incidence of t-MN after [¹⁷⁷Lu]Lu-PSMA therapy. Ongoing follow-up is necessary to further define the true incidence of t-MN or other unexpected delayed toxicities, particularly with earlier use of [¹⁷⁷Lu]Lu-PSMA in the disease course.

Metastasis-directed therapy (MDT) in oligometastatic renal cell carcinoma (RCC) is typically based on conventional imaging. Prostate-specific membrane antigen (PSMA) PET/CT has shown superiority over conventional imaging. Our objective was to perform a proof-of-concept study to evaluate the efficacy of PSMA-guided MDT in oligometastatic RCC. Methods: A PSMA PET/CT database was queried for oligometastatic RCC patients undergoing MDT from 2014 to 2020. The primary endpoint was progression-free survival. Secondary endpoints included freedom from local progression, freedom from change in systemic therapy strategy, and overall survival. Results: A search of 3,095 PSMA PET/CT scans identified 83 RCC patients and 34 receiving MDT to 60 sites. The median follow-up was 4.1 y. Six patients (18%) had synchronous metastatic disease. The median number of metastases was 1 (interquartile range, 1–2). Common sites included bone (19, 32%) and lung (19, 32%). Radiation therapy was delivered to 56 metastases (93%), including stereotactic ablative body and conventional radiotherapy (38 and 18 metastases, respectively), and 4 (7%) underwent surgery. One-, 3-, and 5-y freedom from local progression was 94% (95% CI, 85%–98%), 85% (95% CI, 69%–94%), and 85% (95% CI, 69%–94%), respectively. One-, 3-, and 5-y overall survival was 88% (95% CI, 71%–95%), 71% (95% CI, 52%–84%), and 64% (95% CI, 45%–79%), respectively. One-, 3-, and 5-y progression-free survival was 47% (95% CI, 30%–63%), 26% (95% CI, 13%–42%), and 8% (95% CI, 2%–22%), respectively. One-, 3-, and 5-y freedom from change in systemic therapy strategy was 76% (95% CI, 57%–87%), 65% (95% CI, 45%–79%), and 43% (95% CI, 19%–65%), respectively. Conclusion: In this proof-of-concept study, PSMA-guided MDT provided durable oncologic outcomes for oligometastatic RCC, even at 5 y. To our knowledge, this study had the first cohort uniformly undergoing PSMA-guided MDT and one of the longest follow-ups of MDT for oligometastatic RCC. With increasing availability, PSMA PET/CT can be rapidly instituted to select patients for MDT and improve outcomes for patients with oligometastatic RCC.

The development of resistance significantly hampers the efficacy of immunotherapies in cancer treatment. The combination of JQ1, a BRD4 protein inhibitor, and anti–programmed death ligand 1 (PD-L1) immunotherapies has a synergic therapeutic potential to treat solid tumors. This study aimed to evaluate the potential of immuno-PET imaging for measuring pharmacodynamic biomarkers in response to this combination therapy targeting PD-L1. Methods: We synthesized different radioligands derived from the anti–PD-L1 C4 antibody and a minibody targeting murine CD8α for immuno-PET imaging. We conducted experiments on human non–small cell lung cancer and mouse colorectal carcinoma animal models to assess the efficacy of JQ1 and avelumab treatment on PD-L1 expression and immune cell infiltration by immuno-PET imaging. Taking advantage of the unique properties of the C4-derived minibody, we measured PD-L1 occupancy in tumors after treatment. Results: JQ1 efficiently reduced PD-L1 extracellular expression across all tested cell lines in vitro and in vivo. Avelumab and JQ1 treatments alone or in combination led to significant tumor growth reduction in the immunocompetent murine colorectal carcinoma model, reducing mean tumor growth from 725% in the control group to 125% in the combination group. Treatments also significantly increased the survival of mice by 4–12 d compared with the control group. Although imaging CD8-positive T-cell infiltration did not predict tumoral response, imaging the unoccupied fraction of PD-L1 after treatment was predictive of tumor growth reduction and survival. Conclusion: Immuno-PET imaging with noncompetitive radioligands throughout the treatment course could improve the efficiency and support rationalization of the dosing regimen of immunotherapies.

We previously demonstrated that a deep learning (DL) model of myocardial perfusion SPECT imaging improved accuracy for detection of obstructive coronary artery disease (CAD). We aimed to improve the clinical translatability of this artificial intelligence (AI) approach using the results to derive enhanced total perfusion deficit (TPD) and 17-segment summed scores. Methods: We used a cohort of patients undergoing myocardial perfusion imaging within 180 d of invasive coronary angiography. Obstructive CAD was defined as any stenosis of at least 70% or at least 50% in the left main coronary artery. We used per-vessel DL predictions to modulate polar map pixel scores. These transformed polar maps were then used to derive TPD-DL and summed stress score–DL. We compared diagnostic performance using area under the receiver operating characteristic curve (AUC). Results: In the 555 patients held out for testing, the median age was 65 y (interquartile range, 57–73 y), and 381 (69%) were male. Obstructive CAD was present in 329 (59%) patients. The prediction performance for obstructive CAD of stress TPD-DL (AUC, 0.837; 95% CI, 0.804–0.870) was higher than AI prediction alone (AUC, 0.795; 95% CI, 0.758–0.831; P = 0.005) and traditional stress TPD (AUC, 0.737; 95% CI, 0.696–0.778; P < 0.001). Summed stress score–DL had the second highest prediction performance (AUC, 0.822; 95% CI, 0.788–0.857) and higher AUC than traditional quantitative summed stress score (AUC, 0.728; 95% CI, 0.686–0.769; P < 0.001). At a threshold of 5%, the sensitivity and specificity of TPD rose from 72% to 79% and from 62% to 70%, respectively. Conclusion: Integrating AI predictions with traditional quantitative approaches leads to a simplified AI approach, presenting clinicians with familiar measures but operating with higher accuracy than traditional quantitative scoring. This approach may facilitate integration of new AI methods into clinical practice.

[¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)–617 is a standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and an androgen receptor pathway inhibitor. However, for many, responses are short and progression is inevitable. Contributing factors to treatment resistance include molecular heterogeneity with variable PSMA expression, micrometastases that may not absorb sufficient radiation from ¹⁷⁷Lu to result in cell death, and inherent or acquired radioresistance because of genomic alterations or the tumor microenvironment. Cabazitaxel is a radiosensitizer and may treat PSMA-negative disease that would otherwise evade targeting by [¹⁷⁷Lu]Lu-PSMA-617. We hypothesize that the combination of [¹⁷⁷Lu]Lu-PSMA-617 and cabazitaxel will be synergistic with an acceptable safety profile. Methods: This investigator-initiated phase I–II trial aims to evaluate the safety, tolerability, and preliminary efficacy of cabazitaxel and [¹⁷⁷Lu]Lu-PSMA-617 in combination. Up to 38 patients with mCRPC will receive up to 6 doses of [¹⁷⁷Lu]Lu-PSMA-617 administered intravenously every 6 wk at a fixed dose of 7.4 GBq. Cabazitaxel will be administered concurrently (dose range, 12.5–20 mg/m²) on day 2 and day 23 of each 6-wk cycle, with dose escalation determined using a traditional 3 + 3 design to establish the maximum tolerated or administered dose. Key eligibility criteria include a diagnosis of progressive mCRPC with PSMA-positive disease on PSMA PET/CT (SUV_max ≥ 15) and no sites of discordance on [¹⁸F]F-FDG PET/CT. Patients must have received prior docetaxel and an androgen receptor pathway inhibitor, have adequate bone marrow and organ function, and have an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary objective is to assess for dose-limiting toxicities and determine the recommended phase II dose of cabazitaxel and [¹⁷⁷Lu]Lu-PSMA-617 in combination. Secondary objectives include further safety evaluation through the measurement of the frequency and severity of adverse events, assessment of efficacy, and evaluation of changes in pain and health-related quality of life over the first 12 mo from treatment commencement. Plasma will be collected at baseline, during treatment, and at disease progression for circulating tumor DNA analysis, which will be correlated with clinical outcomes to identify potential biomarkers of treatment response or resistance. Conclusion: Enrollment commenced in August 2022, with anticipated completion in 2025.

Despite improvements in neuroblastoma treatment, survival figures lag behind those of many other childhood malignancies. New treatments, and better use of existing treatments, are essential to reduce mortality. Neuroblastoma expresses several molecular targets for radionuclide imaging and therapy, of which the most widely exploited is the norepinephrine transporter. [¹²³I]metaiodobenzylguanidine (MIBG) imaging and [¹³¹I]MIBG treatment, which target this physiologic pathway, have been in clinical practice for 40 y. Although therapy outcomes have been favorable, [¹³¹I]MIBG use has not yet been optimized. Somatostatin receptors and the disialoganglioside are alternative targets, but their use remains experimental. The charity Children’s Cancer Research Fund organized a workshop bringing together a broad range of scientists including radiochemists, radiobiologists, radiation physicists, clinical researchers including pediatric oncologists and nuclear medicine physicians, and patient advocates from the United Kingdom, United States, and continental Europe to share their experiences with molecular imaging and radiotherapy of neuroblastoma and discuss potential ways of improving treatment outcomes and access. These include development of alternative vectors targeting somatostatin receptors and disialoganglioside, isotopes such as α-particle and Auger electron emitters with different radiation characteristics, and combinations with external-beam radiotherapy, immunotherapy, and DNA damage repair inhibitors. Barriers to progress discussed included the unpredictable radioisotope supply, production of novel radiopharmaceuticals, lack of data regarding which are the best combination therapies, and insufficient clinical facilities. The aim was to stimulate the development and assessment of more effective treatments.

Detection of positive resection margins in surgical procedures of high-risk prostate cancer is key for minimizing the risk of recurrence. This study aimed at evaluating the accuracy of functional tumor-volume segmentation in intraoperative ex vivo PET/CT for margin assessment in prostate cancer patients undergoing radical prostatectomy. Methods: Seven high-risk prostate cancer patients received [¹⁸F]PSMA-1007 before radical prostatectomy. After removal of the prostate gland, ex vivo imaging on the AURA 10 PET/CT system was performed, and functional tumor volume was segmented using 4 semiautomatic segmentation methods. Resection margins and volumes were compared with histopathology. Additionally, a supportive phantom study was conducted to assess segmentation accuracy at low radiopharmaceutical activity. Results: Clinically, 18 lesions were analyzed in intraoperative PET/CT. Sensitivity, specificity, and positive and negative predictive values of margin detection were 83%, 100%, 100%, and 92%, respectively, using an iterative thresholding method. In 1 patient, a biochemical recurrence was observed within 1 y of prostate-specific antigen follow-up, and 1 patient underwent adjuvant radiotherapy. The remaining 5 patients were still undergoing prostate-specific antigen follow-up with no evidence of biochemical recurrence. On the basis of a phantom-deduced minimal segmentable activity concentration of approximately 2 kBq/mL, we propose an administered [¹⁸F]PSMA-1007 activity of at least 1.9 and 0.4 MBq/kg for preoperative and intraoperative injections, respectively. Conclusion: Intraoperative ex vivo PET/CT is a promising modality for intraoperative margin assessment. Prospective trials are needed to further investigate the value of specimen PET/CT-based radioguided surgery in high-risk prostate cancer.