AI based segmentation for dosimetry

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Manual versus artificial intelligence-based segmentations as a pre-processing step in whole-body dosimetry calculations (conference abstract)

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Manual vs AI based segmentation for dosimetry

Manual versus artificial intelligence-based segmentations as a pre-processing step in whole-body dosimetry calculations

by Joyce van Sluis, Walter Noordzij, Lars Edenbrandt, Elisabeth G. E. de Vries, Adrienne H. Brouwers, and Ronald Boellaard


Poster presentation at the EANM 2021 conference

Abstract

Aim/Introduction

Over the last decades, labelling of monoclonal antibodies (MAbs) with zirconium-89 (89Zr) allowed whole body assessment of MAb distribution and tumour targeting over time with molecular imaging. The main advantage of 89Zr is the long half-life of 78.4 h matching the pharmacokinetic behaviour of antibodies, making it suitable for labelling of MAbs.     
The long physical half-life of 89Zr and the long biological half-life of MAbs may cause high radiation burden and/or limits the amount of activity that can be administered, which in turn limits image quality. It is therefore important to obtain reliable radiation dose estimates to optimize the amount of activity that can be administered while keeping radiation burden within acceptable limits.
Organ segmentation is required for whole-body dosimetry but is a very time-consuming task. Therefore, we explored the possibility of using an AI based automated segmentation tool as a pre-processing step for calculating the organ and whole-body effective doses. 

Materials and Methods

Retrospective PET/CT data of six patients undergoing treatment with 89Zr-labelled pembrolizumab were included in this study. Manual organ segmentations were performed using in-house developed software and biodistribution information was obtained. Using the activity biodistribution information, residence times were calculated. The obtained residence times served as input for OLINDA XLM version 1.0 (Vanderbilt University, 2003) to calculate the effective dose per organ as well as the whole-body effective dose (mSv/MBq) according to ICRP60 and ICRP103 guidelines.     
Subsequently, organ segmentations were also performed using Recomia, a cloud-based AI platform for nuclear medicine and radiology research. The workflow for calculating residence times and whole-body effective doses, as described above, was repeated. 

Results

Patient data were obtained at three different time-points, day 2, 4, and 7 postinjecton, resulting in 18 PET/CT scans. Overall analysis time was approximately half a workday for manual segmentations compared to ≤30 min using Recomia. Whole-body effective doses differed minimally for the six patients with a median difference in received mSv/MBq of 0.49% (range 0.12 – 1.58%) according to ICRP60 and 0.52% (range 0.15 – 1.95%) according to ICRP103.

Conclusion

These first results suggest that whole-body dosimetry calculations can benefit from fast automated AI based whole-organ segmentations using Recomia. As newly developed MAbs are quickly emerging in anti-cancer therapy, whole-body effective doses for these different therapeutic agents can be assessed quickly and efficiently.

Manual vs AI based segmentation for dosimetry
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Zr-Pembro to assess PD-1 block in patients

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89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

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89Zr-Pembrolizumab to assess clinical PD-1 Block

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

by II.C.Kok, J.S.Hooiveld, P.P.van de Donk, D.Giesen, E.L.van der Veen, M.N.Lub-de Hooge, A.H.Brouwers, T.J.N.Hiltermann, A.J.van der Wekken, L.B.M.Hijmering-Kappelle, W.Timens, S.G.Elias, G.A.P.Hospers, H.J.M.Groen, W.Uyterlinde, B.van der Hiel, J.B.Haanen, D.J.A.de Groot, M.Jalving, E.G.E.de Vries


Annals of Oncology. 2022, 33(1), 80. doi: 10.1016/j.annonc.2021.10.213

Abstract

Background
Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.

Patients and methods
Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.

Results
Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.

Conclusion
89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

89Zr-Pembrolizumab to clinically assess PD-1 blockade
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Uptake of Pembrolizumab in lymphoid organs

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89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

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Uptake of Pembrolizumab in lymphoid organs 

89Zr-pembrolizumab biodistribution is influenced by PD-1-mediated uptake in lymphoid organs

Elly L van der Veen, Danique Giesen, Linda Pot-de Jong, Annelies Jorritsma-Smit, Elisabeth G E De Vries, and Marjolijn N Lub-de Hooge

 

J Immunother Cancer. 2020; 8(2): e000938. doi: 10.1136/jitc-2020-000938

Abstract

Background
To better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.

Methods
Humanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.

Results
PET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.

Conclusion
89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.
 

Uptake of Pembrolizumab in lymphoid organs
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Bimodal PET/NIRF imaging of HER-2 tumors

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Site-specific, platform-based dual-labeled immunoconjugate for bimodal PET/NIRF imaging of HER2-positive tumors (conference Abstract)

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Biomodal PET/NIRF Imaging of her-2 tumors

Site-specific, platform-based dual-labeled immunoconjugate for bimodal PET/NIRF imaging of HER2-positive tumors

Pierre Adumeau, René Raavé, Milou Boswinkel, Sandra Heskamp, Mathieu Moreau, Claire Bernhard, Laurène Da Costa, Victor Goncalves, Franck Denat


EMIM Conference 2020

Abstract

Introduction 
Immuno-PET/NIRF imaging is very promising for cancer therapy, as it allows non-invasive localization of the tumor and its image-guided resection. The mostly used strategy to synthesize such dual-labeled conjugates relies on a double, sequential random conjugation of the fluorophore and the radionuclide/chelator with the antibody. However, the random conjugation leads to high heterogeneity and potential loss of bioactivity and these phenomena are exponentially amplified by sequential modifications. Therefore, there is a need for a better dual-labeling strategy for PET/NIRF imaging.

Results/Discussion 
The trivalent platform BCN-DFO-IR800 was obtained in a five steps synthetic route with a global yield of 5%. Trastuzumab-N3, obtained through chemoenzymatic glycoengineering, was efficiently conjugated with the trivalent platform, leading to trastss-DFO/IR800 with a degree of labeling (DOL) of 2.0 (theoretical maximum). Trastrd-DFO/IR800 was synthesized with comparable DOL for the sake of comparison.
Radiolabeling of the conjugates with 89Zr yielded the radioconjugates with high yield, purity and specific activity (RCY >95%, RCP >99%, SA >50 MBq/mg).
The site-specific conjugate displayed lesser aggregation over time than its random cousin (after 7 days in PBS: 5.0±0.1 % vs 12.7±5.2 % for trastss-DFO/IR800 and trastrd-DFO/IR800, respectively). Fluorescence intensity of the site-specific conjugate also showed an improved stability compared to the random conjugate, the first displaying 90±1 % of the initial fluorescence intensity after 7 days in PBS, with only 25±3 % for trastrd-DFO/IR800.

Conclusion 
This is the first example of a platform-based, site-specific PET/NIRF conjugate. This strategy gives complete control over the dual-labeling of antibody. The preliminary results have demonstrated the in vitro superiority of our conjugate over the classical random bimodal conjugate. We expect these results to translate into a superior in vivo behavior of the site-specific conjugate. In vivo experiment results will be presented at the conference.
 

Bimodal PET/NIRF Imaging of HER-2 Tumors
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Development of IL2 derived PET tracer

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Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

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IL2 PET Tracers for imaging mouse T-cells

Development and Evaluation of Interleukin-2–Derived Radiotracers for PET Imaging of T Cells in Mice

Elly L. van der Veen, Frans V. Suurs, Frederik Cleeren, Guy Bormans, Philip H. Elsinga, Geke A.P. Hospers, Marjolijn N. Lub-de Hooge, Elisabeth G.E. de Vries, Erik F.J. de Vries and Inês F. Antunes

Journal of Nuclear Medicine Sept. 2020, 6(9) 1355-1360; DOI:10.2967/jnumed.119.238782

Abstract

Recently, N-(4-18F-fluorobenzoyl)-interleukin-2 (18F-FB-IL2) was introduced as a PET tracer for T cell imaging. However, production is complex and time-consuming. Therefore, we developed 2 radiolabeled IL2 variants, namely aluminum 18F-fluoride-(restrained complexing agent)-IL2 (18F-AlF-RESCA-IL2) and 68Ga-gallium-(1,4,7-triazacyclononane-4,7-diacetic acid-1-glutaric acid)-IL2 (68Ga-Ga-NODAGA-IL2), and compared their in vitro and in vivo characteristics with 18F-FB-IL2. 

Methods: Radiolabeling of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 was optimized, and stability was evaluated in human serum. Receptor binding was studied with activated human peripheral blood mononuclear cells (hPBMCs). Ex vivo tracer biodistribution in immunocompetent BALB/cOlaHsd (BALB/c) mice was performed at 15, 60, and 90 min after tracer injection. In vivo binding characteristics were studied in severe combined immunodeficient (SCID) mice inoculated with activated hPBMCs in Matrigel. Tracer was injected 15 min after hPBMC inoculation, and a 60-min dynamic PET scan was acquired, followed by ex vivo biodistribution studies. Specific uptake was determined by coinjection of tracer with unlabeled IL2 and by evaluating uptake in a control group inoculated with Matrigel only. 

Results: 68Ga-Ga-NODAGA-IL2 and 18F-AlF-RESCA-IL2 were produced with radiochemical purity of more than 95% and radiochemical yield of 13.1% ± 4.7% and 2.4% ± 1.6% within 60 and 90 min, respectively. Both tracers were stable in serum, with more than 90% being intact tracer after 1 h. In vitro, both tracers displayed preferential binding to activated hPBMCs. Ex vivo biodistribution studies on BALB/c mice showed higher uptake of 18F-AlF-RESCA-IL2 than of 18F-FB-IL2 in liver, kidney, spleen, bone, and bone marrow. 68Ga-Ga-NODAGA-IL2 uptake in liver and kidney was higher than 18F-FB-IL2 uptake. In vivo, all tracers revealed uptake in activated hPBMCs in SCID mice. Low uptake was seen after a blocking dose of IL2 and in the Matrigel control group. In addition, 18F-AlF-RESCA-IL2 yielded the highest-contrast PET images of target lymph nodes. 

Conclusion: Production of 18F-AlF-RESCA-IL2 and 68Ga-Ga-NODAGA-IL2 is simpler and faster than that of 18F-FB-IL2. Both tracers showed good in vitro and in vivo characteristics, with high uptake in lymphoid tissue and hPBMC xenografts.

IL2 PET TRACERS FOR IMAGING MOUSE T-CELLS
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89Zr-Immuno-Positron Emission Tomography in Oncology

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89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

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89Zr Radiochemistry Review

89Zr-Immuno-Positron Emission Tomography in Oncology: State-of-the-Art 89Zr Radiochemistry.

Heskamp S, Raavé R, Boerman O, Rijpkema M, Goncalves V, Denat F.


Bioconjug Chem. 2017 Aug 24. doi: 10.1021/acs.bioconjchem.7b00325.

Abstract

Immuno-positron emission tomography (immunoPET) with 89Zr-labeled antibodies has shown great potential in cancer imaging. It can provide important information about the pharmacokinetics and tumor-targeting properties of monoclonal antibodies and may help in anticipating on toxicity. Furthermore, it allows accurate dose planning for individualized radioimmunotherapy and may aid in patient selection and early-response monitoring for targeted therapies. The most commonly used chelator for 89Zr is desferrioxamine (DFO). Preclinical studies have shown that DFO is not an ideal chelator because the 89Zr–DFO complex is partly unstable in vivo, which results in the release of 89Zr from the chelator and the subsequent accumulation of 89Zr in bone. This bone accumulation interferes with accurate interpretation and quantification of bone uptake on PET images. Therefore, there is a need for novel chelators that allow more stable complexation of 89Zr. In this Review, we will describe the most recent developments in 89Zr radiochemistry, including novel chelators and site-specific conjugation methods.

89ZR RADIOCHEMISTRY REVIEW
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In vitro and in vivo comparison of the novel

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In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

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Conference Abstract: DFO-cyclo versus DFO

In vitro and in vivo comparison of the novel 89Zr chelator DFO-cyclo* with DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


ESRR 18, 19th European Symposium on Radiopharmacy and Radiopharmaceuticals, 05-08 April 2018, Groningen, Netherlands

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation of 89Zr in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: DFO-CYCLO VERSUS DFO
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In vitro and in vivo evaluation of novel 89Zr-chelators

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In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

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Conference Abstract: 89Zr chelate evaluation

In vitro and in vivo evaluation of novel 89Zr-chelators (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Adrien Dubois, Laurene Da Costa, Victor Goncalves, Franck Denat


Third international edition of the symposium on Technetium and Other Radiometals in Chemistry and Medicine (TERACHEM 2018), September 26-29, 2018, Bressanone (BZ), Italy

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO).1 Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for more stable 89Zr chelators.

CONFERENCE ABSTRACT: 89ZR CHELATE EVALUATION
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Development and evaluation of a new Interleukin

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Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

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Conference Abstract: IL-2 PET

Development and evaluation of a new Interleukin-2 PET radioligand Al[18F]RESCA-IL2: comparison with [18F]FB-IL2 (Conference Abstract)

I.F. Antunes, E.L. van der Veen, E.E.M. Deneer, F. Cleeren, G. Bormans, P.H Elsinga, R.A.J.O. Dierckx, E.G.E de Vries, E.F.J. de Vries


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Düsseldorf

 

Aim

Interleukin-2 is a 15.5 kDa glycoprotein that binds with high affinity to IL2 receptors (IL2R) that are overexpressed on activated T-cells, which are involved in various pathological diseases, such as autoimmune diseases, but also play a major role in the tumor immune response. We have developed 18F-FB-IL2 which has been successfully used for detecting activated T-cells in rodents [1]. Recently, a GMP-compliant production of 18F-FB-IL2 for clinical use was implemented, but the production method proved to be complex and time-consuming. Therefore, we now developed a simplified method to label IL2 with 18F. Here we present the synthesis of Al 18F-RESCA-IL2 and its comparison to 18F-FB-IL2.

CONFERENCE ABSTRACT: IL-2 PET
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Evaluation of the in vitro and in vivo characteristics

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Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

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Conference Abstract: Novel 89Zr chelator

Evaluation of the in vitro and in vivo characteristics of the novel89Zr-octacoordinated chelator DFO-cyclo* compared to the hexacoordinated DFO (Conference Abstract)

Rene Raave, Gerwin Sandker, Sandra Heskamp, Otto Boerman, Mark Rijpkema, Floriane Mangin, Michel Meyer, Jean-Claude Chambron, Mathieu Moreau, Claire Bernhard, Victor Goncalves, Franck Denat


31st Annual Congress of the European Association of Nuclear Medicine, 13-17 October 2018, Duesseldorf

Abstract

The current “gold standard” chelator to label antibodies with 89Zr for immunoPET is desferrioxamine (DFO). Preclinical studies have shown that the 89Zr-DFO complex is partly unstable in vivo, resulting in release of 89Zr and subsequent accumulation in mineral bone tissue. This bone uptake may prevent the detection of bone metastases, and hampers accurate estimation of the radiation dose to the bone marrow in dose planning for radioimmunotherapy. Therefore, there is a need for a more stable 89Zr chelator. Here we report DFO-cyclo*, a preorganized extended DFO derivative introducing an octacoordination, and investigate the stability of its 89Zrr complex over the unsaturated hexacoordinated 89Zr-DFO complex in vitro and in vivo.

CONFERENCE ABSTRACT: NOVEL 89ZR CHELATOR
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