Purpose This study aimed to investigate theranostic strategies in colorectal and skin cancer base... more Purpose This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively. Methods We designed F(ab′) 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab′) 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab′) 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab′) 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results Radiolabeling procedure did not change F(ab′) 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab′) 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′) 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab′) 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab′) 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions 111 In-DOTAGA-F(ab′) 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab′) 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.
Copyright and moral rights for the publications made accessible in the public portal are retained... more Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
SO2 reaction with electrophilic species present in wine, including in particular carbonyl compoun... more SO2 reaction with electrophilic species present in wine, including in particular carbonyl compounds, is responsible for the reduction of its protective effect during wine aging. In the present study, direct 1H NMR profiling was used to monitor the reactivity of SO2 with acetaldehyde under wine-like oxidation conditions. The dissociation of acetaldehyde bound SO2 was evidenced suggesting that released free SO2 can further act as an antioxidant. EPR and DPPH assays showed an increasing antioxidant capacity of wine with the increase in the concentration of acetaldehyde sulfonate. The presence of acetaldehyde sulfonate in wines was correlated with the overall antioxidant activity of wines. The first evidence of acetaldehyde bound SO2 dissociation provides a completely new representation of the long-term protection efficiency of SO2 during bottle aging.
ABSTRACT Palladium-catalyzed amination was successfully applied to the synthesis of macrobicyclic... more ABSTRACT Palladium-catalyzed amination was successfully applied to the synthesis of macrobicyclic cryptands comprising cyclen or cyclam and pyridine moieties. Starting bis(halopyridylmethyl) substituted cyclen and cyclam were obtained from protected tetraazamacrocycles in good yields and introduced in the catalytic macrocyclization reactions with a number of polyamines and oxadiamines to give target macrobicycles. The yields of macrobicyclic cryptands were shown to be dependent on the cavity size of starting tetraazamacrocycle, on the nature of halogen atom and substitution pattern in the starting compounds, and on the nature of di- and polyamines. The best yields reached 33%.
IntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently... more IntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy.1 These nanoparticles consist of a polysiloxane network surrounded by Gd chelates. Nanoparticles, which contain high-Z contrast agents such as Gd-based nanoparticles, increase the sensitivity of the tumor to radiation. Owing to their small size (3 +/- 0.1 nm), AGuIX® typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes.2 Multi-imaging properties and safety evaluation of the Gd-based nanoparticles have been investigated before their clinical transfer. MethodsGd-based nanoparticles have been administrated to rats-bearing tumor and non-human primates for MRI and PET investigations. In parallel, regulatory investigations have been performed on both rodents and non-human primates.
Une nouvelle voie d'acces a des bis-polyazamacrocycles est decrite. Elle est realisee par con... more Une nouvelle voie d'acces a des bis-polyazamacrocycles est decrite. Elle est realisee par condensation d'un intermediaire N,N'N-triboctetraazamacrocycle ou N,N'-diboctriazamacrocycle avec un derive bis-electrophile de l'o-, m-, p-zylene, ou de l'anthracene. L'utilisation du groupement protecteur tert-butyloxycarbonyle (Boc), aisement elimine par action de HCl 6 M ou du TFA, permet d'obtenir les synthons proteges. Les derives bismacrocycliques pontes par un groupement anthracenyle ou o-zylenyle sont prepares au depart des precurseurs dichlorure d'acide : les diamides ainsi formes sont reduits par BH 3 -THF puis la deprotection est effectuee par un traitement acide. La N-alkylation des macrocycles proteges par le 1,3- ou 1,4-bis(bromomethyl)benzene conduit aux bis-macrocycles correspondants, et les composes cibles sont obtenus apres acidification du milieu. Des mesures par RPE de la distance spin-spin pour les complexes de cuivre ont ete effectuees ...
Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold n... more Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold nanoparticles (AuNP) represent a promising approach in the diagnosis and the treatment of tumors. However, their poor pharmacokinetic profile, especially their rapid renal clearance prevents from an efficient exploitation of their potential for medical applications. The present study focuses on a strategy which resides in the encapsulation of AuNP in large polymeric NP to avoid the glomerular filtration and then to prolong the vascular residence time. An original encapsulation procedure using the polyethyleneimine (PEI) was set up to electrostatically entrap AuNP in biodegradable poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol -PLGA (PLGA-PEG) NP. Hydrodynamic diameters of NP were dependent of the PEI/Au ratio and comprised between 115 and 196 nm for ratios equal or superior to 4. Encapsulation yield was close to 90 % whereas no loading was observed without PEI. No toxicity was observed after 24 h exposure in hepatocyte cell-lines. Entrapement of AuNP in polymeric nanocarriers facilitated the passive uptake in cancer cells after only 2 h incubation. In healthy rat, the encapsulation allowed increasing the gold concentration in the blood within the first hour after intravenous administration. Polymeric nanoparticles were sequestered in the liver and the spleen rather than the kidneys. T1-weighted magnetic resonance demonstrated that encapsulation process did not alter the contrast agent properties of gadolinium. The encapsulation of the gold nanoparticles in PLGA particles paves the way to innovative imaging-guided anticancer therapies in personalized medicine.
Metallic complexes of macrocycles chelators 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) a... more Metallic complexes of macrocycles chelators 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthetized with iron (III) giving Fe(III)-DOTA and Fe(III)-NOTA complexes. They were studied in comparison of ferricyanide and ferrocenemethanol on cyclic voltammetry with glassy carbon working electrode (GC) and screen-printed carbon electrode (SPCE). Diffusion coefficients and heterogeneous electron transfer rate constants were determined with Randles-Sevcik and Nicholson-Lavagnini methods. Using SPCE. The average values of diffusion coefficient and transfer rate constant were respectively of 1.34 × 10−6 cm2 s−1 and 1.01 × 10−3 cm s−1 for Fe(III)-DOTA, and 4.32 × 10−6 cm2 s−1 and 1.14 × 10−3 cm s−1 for Fe(III)-NOTA. Interestingly, characteristics of the synthetized complexes on SPCE compete advantageously with those of ferricyanide and ferrocenemethanol, making Fe(III)-DOTA and Fe(III)-NOTA potential markers for future biosensors development.
A novel and simple route to synthesize ultrasmall silica nanoparticles having hydrodynamic diamet... more A novel and simple route to synthesize ultrasmall silica nanoparticles having hydrodynamic diameters under 10 nm for imaging and therapeutic applications.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunotherapies have proven to be highly efficient for cancer treatments and combination with eit... more Immunotherapies have proven to be highly efficient for cancer treatments and combination with either internal vectorized or external radiotherapies can enhance this efficacy through notably increasing tumor immune infiltrate. The clinical evaluation of such combination therapies requires expertise and exquisite processes in multiple fields, immunotherapy, radiotherapy and nuclear medicine. Similarly, this applies into preclinical settings for assessing proof of concept of novel combinations. Herein, we will present our preclinical evaluation process to combine external or internal (i.e. lutetium-177 radiolabeled molecule) radiotherapy with immunotherapies that include radiochemistry, target expression in tissue by autoradiography, in vitro binding evaluation, in vivo tolerance and activity based on single or fractionated treatment doses. The targeted radiotherapy (TRT) is a systemic target-based approach combining a high-affinity receptor-binding ligand radiolabeled with a high-energy beta-emitting radionuclide whereas external 3D image guided radiotherapy targets the shape of the tumors very precisely. Combination studies with immunotherapies in preclinical setting require the selection of appropriate and relevant syngenic or humanized mouse models, driven by target expression, radioresistance (i.e hypoxia), and tumor immune infiltrate (lymphocyte CD8, macrophage etc.). In addition, the therapeutic evaluation should take into consideration the tolerance related to ionizing radiations, the scheduling of treatment (cumulated dose, fractionation), antitumor immune response and monitoring of immune checkpoint target expression. As nuclear imaging is a powerful tool to monitor and predict in vivo target expression and treatment efficacy, TRT is systematically developed in parallel of a PET or SPECT companion diagnostic to visualize and quantify the target expression prior to the treatment with a therapeutic radiolabeled drug. It necessitates the development of radiolabeling processes for either therapeutic or diagnostic purposes and is then performed concomitantly using appropriate bioconjugation strategies suited for theranostic pairs of radionuclides .We will present our recent results that highlight the importance to optimize the external radiotherapy schedule to improve the efficacy and synergistic effect of the association radiotherapy/immunotherapy such as anti-PDL1. Similarly, it is of high interest to combine 177Lu-labeled molecule with immune checkpoint inhibitors in various solid tumors. Transversal skills are mandatory to perform such models and experiments, all being conducted in a dedicated facility for external 3D image guided radiotherapy (SARRP), radiochemistry (hot cells, 177Lu, 68Ga, 64Cu, 89Zr, 111In) and pharmaco-imaging (PET, SPECT, MRI, CT, and optical). Citation Format: Olivier Raguin, Celine Mirjolet, Claire Bernhard, Peggy Provent, Bertrand Collin, Franck Denat, Fabrice Viviani, Alexandre Cochet, Cyril Berthet. Preclinical assessment of external or targeted radiotherapy in combination with immunotherapies and co-development of companion imaging diagnostic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4082.
Purpose This study aimed to investigate theranostic strategies in colorectal and skin cancer base... more Purpose This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively. Methods We designed F(ab′) 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab′) 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab′) 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab′) 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors. Results Radiolabeling procedure did not change F(ab′) 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab′) 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab′) 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab′) 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab′) 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses. Conclusions 111 In-DOTAGA-F(ab′) 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab′) 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.
Copyright and moral rights for the publications made accessible in the public portal are retained... more Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
SO2 reaction with electrophilic species present in wine, including in particular carbonyl compoun... more SO2 reaction with electrophilic species present in wine, including in particular carbonyl compounds, is responsible for the reduction of its protective effect during wine aging. In the present study, direct 1H NMR profiling was used to monitor the reactivity of SO2 with acetaldehyde under wine-like oxidation conditions. The dissociation of acetaldehyde bound SO2 was evidenced suggesting that released free SO2 can further act as an antioxidant. EPR and DPPH assays showed an increasing antioxidant capacity of wine with the increase in the concentration of acetaldehyde sulfonate. The presence of acetaldehyde sulfonate in wines was correlated with the overall antioxidant activity of wines. The first evidence of acetaldehyde bound SO2 dissociation provides a completely new representation of the long-term protection efficiency of SO2 during bottle aging.
ABSTRACT Palladium-catalyzed amination was successfully applied to the synthesis of macrobicyclic... more ABSTRACT Palladium-catalyzed amination was successfully applied to the synthesis of macrobicyclic cryptands comprising cyclen or cyclam and pyridine moieties. Starting bis(halopyridylmethyl) substituted cyclen and cyclam were obtained from protected tetraazamacrocycles in good yields and introduced in the catalytic macrocyclization reactions with a number of polyamines and oxadiamines to give target macrobicycles. The yields of macrobicyclic cryptands were shown to be dependent on the cavity size of starting tetraazamacrocycle, on the nature of halogen atom and substitution pattern in the starting compounds, and on the nature of di- and polyamines. The best yields reached 33%.
IntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently... more IntroductionA new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy.1 These nanoparticles consist of a polysiloxane network surrounded by Gd chelates. Nanoparticles, which contain high-Z contrast agents such as Gd-based nanoparticles, increase the sensitivity of the tumor to radiation. Owing to their small size (3 +/- 0.1 nm), AGuIX® typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes.2 Multi-imaging properties and safety evaluation of the Gd-based nanoparticles have been investigated before their clinical transfer. MethodsGd-based nanoparticles have been administrated to rats-bearing tumor and non-human primates for MRI and PET investigations. In parallel, regulatory investigations have been performed on both rodents and non-human primates.
Une nouvelle voie d'acces a des bis-polyazamacrocycles est decrite. Elle est realisee par con... more Une nouvelle voie d'acces a des bis-polyazamacrocycles est decrite. Elle est realisee par condensation d'un intermediaire N,N'N-triboctetraazamacrocycle ou N,N'-diboctriazamacrocycle avec un derive bis-electrophile de l'o-, m-, p-zylene, ou de l'anthracene. L'utilisation du groupement protecteur tert-butyloxycarbonyle (Boc), aisement elimine par action de HCl 6 M ou du TFA, permet d'obtenir les synthons proteges. Les derives bismacrocycliques pontes par un groupement anthracenyle ou o-zylenyle sont prepares au depart des precurseurs dichlorure d'acide : les diamides ainsi formes sont reduits par BH 3 -THF puis la deprotection est effectuee par un traitement acide. La N-alkylation des macrocycles proteges par le 1,3- ou 1,4-bis(bromomethyl)benzene conduit aux bis-macrocycles correspondants, et les composes cibles sont obtenus apres acidification du milieu. Des mesures par RPE de la distance spin-spin pour les complexes de cuivre ont ete effectuees ...
Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold n... more Due to their imaging and radiosensitizing properties, ultrasmall gadolinium chelate-coated gold nanoparticles (AuNP) represent a promising approach in the diagnosis and the treatment of tumors. However, their poor pharmacokinetic profile, especially their rapid renal clearance prevents from an efficient exploitation of their potential for medical applications. The present study focuses on a strategy which resides in the encapsulation of AuNP in large polymeric NP to avoid the glomerular filtration and then to prolong the vascular residence time. An original encapsulation procedure using the polyethyleneimine (PEI) was set up to electrostatically entrap AuNP in biodegradable poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol -PLGA (PLGA-PEG) NP. Hydrodynamic diameters of NP were dependent of the PEI/Au ratio and comprised between 115 and 196 nm for ratios equal or superior to 4. Encapsulation yield was close to 90 % whereas no loading was observed without PEI. No toxicity was observed after 24 h exposure in hepatocyte cell-lines. Entrapement of AuNP in polymeric nanocarriers facilitated the passive uptake in cancer cells after only 2 h incubation. In healthy rat, the encapsulation allowed increasing the gold concentration in the blood within the first hour after intravenous administration. Polymeric nanoparticles were sequestered in the liver and the spleen rather than the kidneys. T1-weighted magnetic resonance demonstrated that encapsulation process did not alter the contrast agent properties of gadolinium. The encapsulation of the gold nanoparticles in PLGA particles paves the way to innovative imaging-guided anticancer therapies in personalized medicine.
Metallic complexes of macrocycles chelators 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) a... more Metallic complexes of macrocycles chelators 1,4,7-triazacyclononane-N,N,N-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were synthetized with iron (III) giving Fe(III)-DOTA and Fe(III)-NOTA complexes. They were studied in comparison of ferricyanide and ferrocenemethanol on cyclic voltammetry with glassy carbon working electrode (GC) and screen-printed carbon electrode (SPCE). Diffusion coefficients and heterogeneous electron transfer rate constants were determined with Randles-Sevcik and Nicholson-Lavagnini methods. Using SPCE. The average values of diffusion coefficient and transfer rate constant were respectively of 1.34 × 10−6 cm2 s−1 and 1.01 × 10−3 cm s−1 for Fe(III)-DOTA, and 4.32 × 10−6 cm2 s−1 and 1.14 × 10−3 cm s−1 for Fe(III)-NOTA. Interestingly, characteristics of the synthetized complexes on SPCE compete advantageously with those of ferricyanide and ferrocenemethanol, making Fe(III)-DOTA and Fe(III)-NOTA potential markers for future biosensors development.
A novel and simple route to synthesize ultrasmall silica nanoparticles having hydrodynamic diamet... more A novel and simple route to synthesize ultrasmall silica nanoparticles having hydrodynamic diameters under 10 nm for imaging and therapeutic applications.
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Immunotherapies have proven to be highly efficient for cancer treatments and combination with eit... more Immunotherapies have proven to be highly efficient for cancer treatments and combination with either internal vectorized or external radiotherapies can enhance this efficacy through notably increasing tumor immune infiltrate. The clinical evaluation of such combination therapies requires expertise and exquisite processes in multiple fields, immunotherapy, radiotherapy and nuclear medicine. Similarly, this applies into preclinical settings for assessing proof of concept of novel combinations. Herein, we will present our preclinical evaluation process to combine external or internal (i.e. lutetium-177 radiolabeled molecule) radiotherapy with immunotherapies that include radiochemistry, target expression in tissue by autoradiography, in vitro binding evaluation, in vivo tolerance and activity based on single or fractionated treatment doses. The targeted radiotherapy (TRT) is a systemic target-based approach combining a high-affinity receptor-binding ligand radiolabeled with a high-energy beta-emitting radionuclide whereas external 3D image guided radiotherapy targets the shape of the tumors very precisely. Combination studies with immunotherapies in preclinical setting require the selection of appropriate and relevant syngenic or humanized mouse models, driven by target expression, radioresistance (i.e hypoxia), and tumor immune infiltrate (lymphocyte CD8, macrophage etc.). In addition, the therapeutic evaluation should take into consideration the tolerance related to ionizing radiations, the scheduling of treatment (cumulated dose, fractionation), antitumor immune response and monitoring of immune checkpoint target expression. As nuclear imaging is a powerful tool to monitor and predict in vivo target expression and treatment efficacy, TRT is systematically developed in parallel of a PET or SPECT companion diagnostic to visualize and quantify the target expression prior to the treatment with a therapeutic radiolabeled drug. It necessitates the development of radiolabeling processes for either therapeutic or diagnostic purposes and is then performed concomitantly using appropriate bioconjugation strategies suited for theranostic pairs of radionuclides .We will present our recent results that highlight the importance to optimize the external radiotherapy schedule to improve the efficacy and synergistic effect of the association radiotherapy/immunotherapy such as anti-PDL1. Similarly, it is of high interest to combine 177Lu-labeled molecule with immune checkpoint inhibitors in various solid tumors. Transversal skills are mandatory to perform such models and experiments, all being conducted in a dedicated facility for external 3D image guided radiotherapy (SARRP), radiochemistry (hot cells, 177Lu, 68Ga, 64Cu, 89Zr, 111In) and pharmaco-imaging (PET, SPECT, MRI, CT, and optical). Citation Format: Olivier Raguin, Celine Mirjolet, Claire Bernhard, Peggy Provent, Bertrand Collin, Franck Denat, Fabrice Viviani, Alexandre Cochet, Cyril Berthet. Preclinical assessment of external or targeted radiotherapy in combination with immunotherapies and co-development of companion imaging diagnostic [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4082.
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