Journal of nuclear medicine : official publication, Society of Nuclear Medicine最新文献

Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in the treatment of solid tumors, reinforcing the need to elucidate the in vivo biodistribution of these engineered T cells. Here, we integrate the anti-DOTA huC825 reporter ("Thor") platform into newly developed human anti-interleukin-13 receptor α-2 (IL13Rα2)-single-cell fragment variable (scFv)-derived CAR-T cells and investigate its utility for mapping CAR-T cell distribution in a xenograft mouse model of melanoma. Methods: We engineered anti-IL13Rα2-scFv-derived CAR-T cells expressing huC825 (KLG3BBz-huC825), evaluated detection sensitivity, and monitored CAR-T cell biodistribution via weekly [⁸⁶Y]Y-aminobenzyl-DOTA PET/CT and therapeutic efficacy. Results: KLG3BBz-huC825 T cells demonstrated potent antigen-specific cytotoxicity and cytokine release in vitro. The Thor radiohapten capture platform offered exquisite detection sensitivity of only 3,000 engineered T cells and enabled prolonged spatiotemporal assessment of CAR-T cell kinetics up to 7 wk after infusion, corroborated by histopathology. Treatment with KLG3BBz-huC825 resulted in an overall survival benefit. Conclusion: The Thor platform offers a versatile and highly sensitive approach to study the real-time kinetics of CAR-T cells in vivo.

Hepatocellular carcinoma (HCC) ranks among the leading causes of cancer-related mortality worldwide. Although HCC-selective diagnostics and treatments remain limited for late-stage disease, tumor-targeted radiopharmaceuticals offer a promising strategy to address this unmet need. Here, we identify tetraspanin-8 (TSPAN8) as a novel tumor-selective immuno-PET imaging target in HCC. Methods: TSPAN8 expression was analyzed in 4 HCC cell lines (Huh7, Hep3B, SNU182, and SNU449) and 1 hepatoblastoma cell line (HepG2) using Western blotting and flow cytometry. The binding kinetics of a monoclonal antibody (α-hTSPAN8) against human TSPAN8 were evaluated using enzyme-linked immunosorbent assay and biolayer interferometry. Clustered Regularly Interspaced Short Palindromic Repeats/Cas9-mediated gene editing was used to generate TSPAN8-knockout (TSPAN8^-) variants in Huh7 and Hep3B cells, validated through flow cytometry, immunofluorescence, and immunohistochemistry of xenograft tissues. Subcutaneous TSPAN8⁺ and TSPAN8^- xenografts were established in athymic NU/NU mice. For imaging studies, α-hTSPAN8 was conjugated with deferoxamine (DFO) and radiolabeled with ⁸⁹Zr, a positron emitter. Tumor-specific uptake of [⁸⁹Zr]Zr-DFO-α-hTSPAN8 was evaluated by in vivo PET/CT imaging at 48, 72, and 144 h after injection, followed by an ex vivo biodistribution analysis. Results: Huh7 and Hep3B cells exhibited high membrane TSPAN8 expression. The α-hTSPAN8 antibody demonstrated nanomolar affinity and specific binding to TSPAN8⁺ cells. We synthesized both DFO-α-hTSPAN8 and [⁸⁹Zr]Zr-DFO-α-hTSPAN8 to greater than 98% purity and greater than 99% labeling efficiency, respectively, with the radioconjugate exhibiting excellent stability in human serum at 37 °C. In vivo PET/CT imaging and biodistribution studies showed significant and selective tracer accumulation in TSPAN8⁺ tumors, with negligible uptake in TSPAN8^- controls. Conclusion: Our findings establish TSPAN8 as a promising target for radiopharmaceutical development for the treatment of HCC.

Radiopharmaceutical therapy is an emerging approach to treat metastatic disease, with the potential to enable personalized care through imaging. With the growing interest in quantitative imaging, there remains a need for systematic assessment of imageable radionuclides and scanner performance under comparable conditions. This motivated us to quantitatively and qualitatively compare SPECT and PET performance using standardized evaluation procedures to assess their effectiveness in imaging applications for targeted radiotherapy. Methods: The National Electrical Manufacturers Association International Electrotechnical Commission body phantom was used to assess recovery coefficients, contrast, and image quality, including spatial resolution and noise. SPECT performance was evaluated using ^99mTc (a low-energy γ-ray-emitting isotope), ²⁰³Pb (a surrogate for the therapeutic α-particle-emitting ²¹²Pb), and theranostic ¹⁷⁷Lu. PET performance was tested using ¹⁸F, ⁸⁹Zr, and ⁶⁴Cu as imaging surrogates. Results: PET demonstrated superior spatial resolution and accurate activity recovery compared with SPECT, which was limited by lower sensitivity, photon scatter, and collimator design constraints. Among PET isotopes, ¹⁸F showed consistently high quantitative accuracy, whereas ⁸⁹Zr and ⁶⁴Cu performed similarly, with only minor reductions in performance metrics. For SPECT, ^99mTc outperformed ²⁰³Pb and ¹⁷⁷Lu in both lesion detectability and activity recovery. ²⁰³Pb and ¹⁷⁷Lu showed poor quantitative accuracy; however, increasing iterations in reconstruction improved results. Conclusion: These findings underscore the importance of selecting appropriate imaging modalities, isotopes, and reconstruction parameters for theranostic applications. Limitations in quantitative accuracy must be addressed and acknowledged in the search for precise and effective treatment strategies. This study also demonstrates that ²⁰³Pb may serve as a suitable diagnostic partner to ²¹²Pb and validates the use of these quantitative methodologies for the evaluation of PET and SPECT imaging tasks.

Anti-tumor necrosis factor (aTNF) treatment of rheumatoid arthritis (RA) requires 3-6 mo to establish efficacy, with 50%-70% response. Quantitative macrophage-targeting PET/CT previously proved to accurately represent RA activity and treatment response. This study investigated early aTNF treatment efficacy assessment using the [¹¹C]N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide ([¹¹C]DPA-713) macrophage-targeting PET/CT tracer. Methods: Two whole-body [¹¹C]DPA-713 PET/CT scans, at baseline and 4 wk, were performed in 20 patients without exposure to biologic agents before starting aTNF treatment. Tracer uptake in joints was quantified by determination of SUVs in 44 joints at baseline and 4 wk of aTNF treatment. Mean SUVs of all joints and specific joint clusters were related to clinical evaluation of the 44 included joints for tenderness (tender joint count of 44 joints [TJC44]) and swelling (swollen joint count of 44 joints [SJC44]) at 26 wk using linear regression analyses. In addition, multivariable analysis, including both PET/CT and concurrent clinical outcome of independent measures versus dependent TJC44 or SJC44 at 26 wk, was performed. Results: Univariate regression analyses showed significant associations between mean SUV_peak of all joints at baseline (TJC44, r ² = 0.61; SJC44, r ² = 0.50; P < 0.001) and 4 wk (TJC44, r ² = 0.52; SJC44, r ² = 0.48; P < 0.001) and TJC44 or SJC44 at 26 wk. For specific joint clusters, high correlations were found between SUV_peak of metacarpophalangeal joints at 4 wk and SUV_peak of SJC44 at 26 wk (r ² = 0.67; P < 0.001). Multivariable analyses showed slightly increased correlations (r ² ≤ 0.75) by combining PET/CT and TJC44, SJC44, and C-reactive protein measurements. Conclusion: Early quantitative [¹¹C]DPA-713 PET/CT measurements at baseline and 4 wk of aTNF treatment are associated with clinical disease activity at 26 wk. Therefore, quantitative macrophage [¹¹C]DPA-713 PET/CT may have potential clinical value for early prediction of aTNF treatment response in patients with RA.

High-dose ascorbic acid (AA) has shown promise as an adjunctive treatment for various cancers because of its prooxidant cytotoxicity at high concentrations and its multitargeting effects. However, identifying patients who may benefit from AA treatment remains an unmet need, as the therapeutic efficacy of AA is controversial. In this study, we aimed to use an AA analog-6-deoxy-6-¹⁸F-fluoro-l-AA (¹⁸F-FAA)-as a PET tracer and evaluate its uptake in various cancers, exploring its potential clinical application. Methods: This prospective study enrolled 116 patients with histopathologically confirmed malignant tumors who underwent ¹⁸F-FAA PET/CT. Tumors were quantitatively analyzed using the SUV_max, SUV_peak, and tumor-to-background ratio. Results: In total, 23 types of malignant tumors were assessed for their uptake of ¹⁸F-FAA, which was divided into tertiles using SUV_max percentiles. The highest uptake was observed in pheochromocytoma and paraganglioma, glioblastoma, and specific epithelial malignancies (e.g., nasopharyngeal, thyroid, and prostate carcinomas), with a median SUV_max exceeding 12.7, whereas the lowest uptake was found in breast, gastric, bladder, colorectal, and pancreatic cancers (median SUV_max, <8.2). Moderate uptake was noted in melanoma, diffuse large B-cell lymphoma, endometrial cancer, ovarian cancer, non-small cell lung cancer, cervical cancer, tumors of unknown primary origin, germ cell tumors, renal cancer, esophageal cancer, salivary duct carcinoma, malignant peritoneal mesothelioma, and hepatocellular carcinoma. The SUV_peak of these tumors was consistent with these findings. Both primary tumors and metastatic lesions exhibited tumor-specific degrees of ¹⁸F-FAA uptake and image contrast, with higher uptake in metastatic lesions (median SUV_max, 8.1 vs. 9.5, respectively; P = 0.026; tumor-to-background ratio, 12.9 vs. 14.9, respectively; P = 0.045). Conclusion: ¹⁸F-FAA PET/CT demonstrated distinct uptake characteristics across various tumor types and may provide new opportunities for the noninvasive assessment of tumor AA uptake characteristics and AA-based therapy.

Radiopharmaceuticals represent a promising new frontier in cancer therapy. In the United States, cancer is the second leading cause of death. There is an urgent need to develop new therapies to meet this challenge, especially for those patients with advanced and refractory disease. The Society of Nuclear Medicine and Molecular Imaging and Food and Drug Administration convened a "Dose Optimization of Radiopharmaceutical Therapy Developmental Workshop" on May 6 and 7, 2024. Herein, we briefly summarize the highlights from that meeting from the perspective of the stakeholders involved, including multiple representatives from academia, industry, and the Food and Drug Administration. For patients with advanced treatment-refractory solid tumors, the greatest health-related risk is their cancer, rather than long-term toxicity from radiopharmaceutical therapies. In these patients, concerns about long-term nephrotoxicity, marrow toxicity, or the development of second malignancies are of lesser importance given that there is little or no long-term probability of survival. Phase 1 studies that explore dose and schedule are crucial because they set the stage for larger studies that potentially inform regulatory approval.

Liver Imaging Reporting and Data System (LI-RADS) category 3 (LR-3) observations remain indeterminate and often result in repeated follow-up or biopsy. Prostate-specific membrane antigen (PSMA) is overexpressed in hepatocellular carcinoma (HCC) neovasculature and may serve as a useful imaging biomarker. This study aimed to evaluate whether [⁶⁸Ga]Ga-PSMA-11 PET/MRI improved characterization of LR-3 observations in patients with cirrhosis compared with MRI alone. Methods: In this prospective study, conducted between March 2022 and June 2024, 19 patients with cirrhosis and 54 LR-3 observations identified on prior MRI underwent [⁶⁸Ga]Ga-PSMA-11 PET/MRI. An observation was classified as HCC if it demonstrated focal ⁶⁸Ga-PSMA uptake greater than background liver combined with at least 1 LI-RADS major or ancillary feature. The reference standard was histopathology or a follow-up MRI within 12 mo. Diagnostic metrics were calculated. Univariable logistic regression and decision tree analysis were performed to identify imaging predictors of malignancy. Results: Of the 54 LR-3 observations, 13 (24%) were confirmed as HCC and 41 (76%) as benign. [⁶⁸Ga]Ga-PSMA-11 PET/MRI correctly identified 12 of 13 HCCs (sensitivity, 92%; 95% CI, 66.7-99.6) and 39 of 41 benign observations (specificity, 95%; 95% CI, 81.9-99.3). Overall diagnostic accuracy was 94%, with a positive predictive value of 86% and negative predictive value of 97%. Diagnostic performance was significantly better than MRI alone (McNemar test, P < 0.001). [⁶⁸Ga]Ga-PSMA-11 uptake was the only significant imaging predictor of malignancy on univariable analysis (odds ratio, 5.7; P = 0.017). Decision tree analysis identified [⁶⁸Ga]Ga-PSMA-11 uptake, observation size, and hepatobiliary phase hypointensity as principal discriminators. Conclusion: [⁶⁸Ga]Ga-PSMA-11 PET/MRI demonstrates high diagnostic accuracy in differentiating malignant from benign LR-3 liver observations in patients with cirrhosis. This technique may reduce unnecessary follow-up imaging and biopsy. These results support further validation of [⁶⁸Ga]Ga-PSMA-11 PET/MRI as a promising imaging approach for indeterminate liver observations.