Dataset Information

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a Triple-Negative Breast Cancer Patient.

ABSTRACT: INTRODUCTION:CLR1404 is a theranostic molecular agent that can be radiolabeled with 124I (CLR 124) for positron emission tomography (PET) imaging, or 131I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dose escalation clinical trial. MATERIALS AND METHODS:Three-dimensional PET/CT images were acquired at 1, 3, 24, 48, and 120?h postinjection of 178?MBq CLR 124. One month later, pretherapy 2D whole-body planar images were acquired at 0.25, 5, 24, 48, and 144?h postinjection of 370?MBq CLR 131. Following the therapeutic administration of 1990?MBq CLR 131, 3D SPECT/CT images were acquired at 74, 147, 334, and 505?h postinjection. The therapeutic CLR 131 voxel-level absorbed dose was estimated from PET (RAPID PET) and SPECT (RAPID SPECT) images using a Geant4-based Monte Carlo dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry), and region of interest (ROI) mean doses were also estimated using the OLINDA/EXM software based on PET (OLINDA PET), SPECT (OLINDA SPECT), and planar (OLINDA planar) images. RESULTS:The RAPID PET and OLINDA PET tracer-predicted ROI mean doses correlated well (m???0.631, R2 ? 0.694, p???0.01) with both the RAPID SPECT and OLINDA SPECT therapeutic mean doses. The 2D planar images did not have any significant correlations. The ROI mean doses differed by -4% to -43% between RAPID and OLINDA/EXM, and by -19% to 29% between PET and SPECT. The 3D dose distributions and dose volume histograms calculated with RAPID were similar for the PET/CT and SPECT/CT. CONCLUSIONS:This pilot study demonstrated that CLR 124 pretreatment PET images can be used to predict CLR 131 3D therapeutic dosimetry better than CLR 131 2D planar images. In addition, unlike OLINDA/EXM, Monte Carlo dosimetry methods were capable of accurately predicting dose heterogeneity, which is important for predicting dose-response relationships and clinical outcomes.

SUBMITTER: Besemer AE

PROVIDER: S-EPMC6383576 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a Triple-Negative Breast Cancer Patient.

Besemer Abigail E AE Grudzinski Joseph J JJ Weichert Jamey P JP Hall Lance T LT Bednarz Bryan P BP

Cancer biotherapy & radiopharmaceuticals 20181023 1

<h4>Introduction</h4>CLR1404 is a theranostic molecular agent that can be radiolabeled with <sup>124</sup>I (CLR 124) for positron emission tomography (PET) imaging, or <sup>131</sup>I (CLR 131) for single-photon emission computed tomography (SPECT) imaging and targeted radionuclide therapy. This pilot study evaluated a pretreatment dosimetry methodology in a triple-negative breast cancer patient who was uniquely enrolled in both a CLR 124 PET imaging clinical trial and a CLR 131 therapeutic dos ...[more]

PMID: 30351218

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Project description:BackgroundImmunotherapy is a valuable option for cancer treatment, and the curative effect of anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using 68Ga-NOTA-Nb109 nanobody. 68Ga-NOTA-Nb109 was generated by radionuclide (68Ga) labeling of Nb109 using a NOTA chelator. To facilitate clinical trials, we explored the optimal dose range of 68Ga-NOTA-Nb109 in BALB/c A375-hPD-L1 tumor-burdened nude mice and C57-hPD-L1 transgenic MC38-hPD-L1 tumor-burdened mice by administration of a single intravenous dose of 68Ga-NOTA-Nb109 and confirmed the dose in cynomolgus monkeys. The biodistribution data of cynomolgus monkey PET images were extrapolated to estimate the radiation dose for the adult male and female using OLINDA2.1 software.Results68Ga-NOTA-Nb109 was stable in physiologic media and human serum. Ex vivo biodistribution studies showed rapid and specific uptake in A375-hPD-L1 or MC38-hPD-L1 tumors. The estimated ED50 was approximately 5.4 µg in humanized mice. The injected mass (0.3-100 µg in nude mice and approximately 1-100 µg in humanized mice) greatly influenced the general biodistribution, with a better tumor-to-background ratio acquired at lower doses of Nb109 (0.3-10 µg in nude mice and approximately 1 µg in humanized mice), indicating maximum uptake in tumors at administered mass doses below the estimated ED50. Therefore, a single 15-μg/kg dose was adopted for the PET/CT imaging in the cynomolgus monkey. The highest specific and persistent uptake of the tracer was detected in the spleen, except the levels in the kidney and urine bladder, which was related to metabolism and excretion. The spleen-to-muscle ratio of the tracer exceeded 10 from immediately to 4 h after administration, indicating that the dose was appropriate. The estimated effective dose was calculated to yield a radiation dose of 4.1 mSv to a patient after injecting 185 MBq of 68Ga-NOTA-Nb109.Conclusion68Ga-NOTA-Nb109 showed specific accumulation in hPD-L1 xenografts in ex vivo biodistribution studies and monkey PET/CT imaging. The dose escalation distribution data provided a recommended dose range for further use, and the safety of the tracer was confirmed in dosimetry studies.

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Dataset Information

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a Triple-Negative Breast Cancer Patient.

Publications

Pretreatment CLR 124 Positron Emission Tomography Accurately Predicts CLR 131 Three-Dimensional Dosimetry in a Triple-Negative Breast Cancer Patient.

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