PD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small ...biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of ...HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1.
HER2-positive mBC patients with IHC3+ or FISH ≥2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with 89Zr-trastuzumab. 18F2-fluoro-2-deoxy-D-glucose (FDG)–PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2–PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant 89Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load ‘positive’); patterns C and D were considered negative (>50% or all of the tumor load ‘negative’). Early FDG–PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2–PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF).
In the 56 patients analyzed, 29% had negative HER2–PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2–PET/CT were 88%/72% and 83%/96% for early FDG–PET/CT. Combining HER2–PET/CT and FDG–PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months n = 12, 95% confidence interval (CI) 1.4–7.6 from those with a TTF of 15 months (n = 25, 95% CI 9.7–not calculable).
Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1.
NCT01565200.
Introduction
Immune-mediated interstitial pneumonitis may be treated with anti-CD20 therapy after failure of conventional therapies. However, clinical response is variable. It was hypothesized that ...autoreactive CD20-positive cells may play an important role in this variability. This prospective study aims to elucidate if imaging of CD20-positive cells in the lungs allows prediction of the response to anti-CD20 treatment.
Methods
Twenty-one patients with immune-mediated interstitial lung disease (ILD) with deteriorated pulmonary function received a dose of 1000 mg rituximab on day 1 and day 14 spiked with a tracer dose of radiolabeled 89Zr-rituximab. PET/CT was performed on days 3 and 6. Standardized uptake values (SUV) were calculated as a measure for pulmonary CD20 expression. Based on pulmonary function tests (PFT), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO), prior to and 6 months after treatment, patients were classified as responder (stable disease or improvement) or non-responder.
Results
Fifteen patients (71%) were classified as responder. Pulmonary 89Zr-rituximab PET SUVmean was significantly correlated with the change in FVC and DLCO (
K
= 0.49 and 0.56, respectively) when using target-to-background ratios, but not when using SUVmean alone. 89Zr-rituximab SUVmean was significantly higher in responders than in non-responders (0.35 SD 0.09 vs. 0.23 SD 0.06;
P
= 0.02).
Conclusion
Rituximab treatment was effective in the majority of patients. As a higher pulmonary uptake of 89Zr-rituximab correlated with improvement of PFT and treatment outcome, 89Zr-rituximab PET imaging may serve as a potential predictive biomarker for anti-CD20 therapy.
Trial registration
Clinicaltrials.gov identifier NCT02251964
The design of a cooperative adaptive cruise-control (CACC) system and its practical validation are presented. Focusing on the feasibility of implementation, a decentralized controller design with a ...limited communication structure is proposed (in this case, a wireless communication link with the nearest preceding vehicle only). A necessary and sufficient frequency-domain condition for string stability is derived, taking into account heterogeneous traffic, i.e., vehicles with possibly different characteristics. For a velocity-dependent intervehicle spacing policy, it is shown that the wireless communication link enables driving at small intervehicle distances, whereas string stability is guaranteed. For a constant velocity-independent intervehicle spacing, string stability cannot be guaranteed. To validate the theoretical results, experiments are performed with two CACC-equipped vehicles. Implementation of the CACC system, the string-stability characteristics of the practical setup, and experimental results are discussed, indicating the advantages of the design over standard adaptive-cruise-control functionality.
Herein, we describe a valuable method for the introduction of the 18FCF3 group into arenes with highly improved specific activity by the reaction of 18Ftrifluoromethane with aryl iodides or aryl ...boronic acids. This 18Ftrifluoromethylation reaction is the first to be described in which the 18FCF3 products are generated in actual trace amounts and can therefore effectively be used as PET tracers. The method shows broad scope with respect to possible aryl iodide and aryl boronic acid substrates, as well as good to excellent conversion. In particular, the 18Ftrifluoromethylation of boronic acids was found to outperform 18Ftrifluoromethylation reactions of halogenated aryl precursors with regard to conversion, reaction conditions, and kinetics.
A quality label: Tracers for positron emission tomography (PET) with a 18FCF3 group directly attached to an arene were synthesized with improved specific activity by the trifluoromethylation of aryl iodides and aryl boronic acids with 18Ftrifluoromethane (see scheme). In particular, the trifluoromethylation of aryl boronic acids proceeded rapidly under mild reaction conditions, thus making this method highly suitable for the production of PET tracers.
Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including ...HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer.
Purpose
The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer’s disease (AD) and the continued discussions around that decision have increased interest in immunotherapy for ...AD and other brain diseases. Reliable techniques for brain imaging of antibodies may guide decision-making in the future but needs further development. In this study, we used
89
Zr-immuno-PET to evaluate the targeting and distribution of a bispecific brain-shuttle IgG based on Adu with transferrin receptor protein-1 (TfR1) shuttling mechanism, mAbAdu-scFab8D3, designated Adu-8D3, as a candidate theranostic for AD. We also validated the
89
Zr-immuno-PET platform as an enabling technology for developing new antibody-based theranostics for brain disorders.
Methods
Adu, Adu-8D3, and the non-binding control construct B12-8D3 were modified with DFO*-NCS and radiolabeled with
89
Zr. APP/PS1 mice were injected with
89
Zr-labeled mAbs and imaged on days 3 and 7 by positron emission tomography (PET).
Ex vivo
biodistribution was performed on day 7, and
ex vivo
autoradiography and immunofluorescence staining were done on brain tissue to validate the PET imaging results and target engagement with amyloid-β plaques. Additionally,
89
ZrZr-DFO*-Adu-8D3 was evaluated in 3, 7, and 10-month-old APP/PS1 mice to test its potential in early stage disease.
Results
A 7-fold higher brain uptake was observed for
89
ZrZr-DFO*-Adu-8D3 compared to
89
ZrZr-DFO*-Adu and a 2.7-fold higher uptake compared to
89
ZrZr-DFO*-B12-8D3 on day 7. Autoradiography and immunofluorescence of
89
ZrZr-DFO*-Adu-8D3 showed co-localization with amyloid plaques, which was not the case with the Adu and B12-8D3 conjugates.
89
ZrZr-DFO*-Adu-8D3 was able to detect low plaque load in 3-month-old APP/PS1 mice.
Conclusion
89
Zr-DFO*-immuno-PET revealed high and specific uptake of the bispecific Adu-8D3 in the brain and can be used for the early detection of Aβ plaque pathology. Here, we demonstrate that
89
Zr-DFO*-immuno-PET can be used to visualize and quantify brain uptake of mAbs and contribute to the evaluation of biological therapeutics for brain diseases.
A new strategy towards (18)Ftrifluoromethyl-containing compounds is developed. (18)Ftrifluoromethane is synthesised in a fast and efficient manner and subsequently used in the reaction with aldehydes ...and ketones forming (18)Ftrifluoromethyl carbinols in good yields.
PDF
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