AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

Treatment of brain metastases by radiotherapy and gadolinium nanoparticles : from preclinical model to human use

L'apparition de métastases cérébrales multiples est une évolution critique de nombreux cancers avec un impact majeur sur la survie globale. Une nouvelle nanoparticule à base de gadolinium, l’AGuIX®, a récemment démontré son efficacité en tant que radiosensibilisant et agent de contraste IRM dans plusieurs études précliniques. L’objectif de cette thèse est d’établir une preuve de concept sur un modèle animal puis de réaliser la première administration chez l’homme de ce nouveau médicament dans le cadre d’un essai de phase 1.La première partie de ce travail a consisté à l’irradiation en 6 MeV après injection d’AGuIX® d’un modèle de rat Fisher porteur du gliome cérébral 9L suivi par IRM. Nous avons mis en évidence une distribution favorable des nanoparticules dans la tumeur par effet EPR (Enhanced Permeability and Retention) avec une concentration de gadolinium dans la tumeur 20 fois plus importante que dans le cerveau sain. L’effet radiosensibilisant a été démontré avec une diminution significative (p=0.02) de la taille des tumeurs dans le groupe irradié après injection d’AGuIX®. Ces résultats, associés au profil de tolérance favorable sur les modèles animaux ont motivés le transfert chez l’homme de ce nouveau médicament dans une étude de phase 1 nommée NANO-RAD (EudraCT 2015-004259-30 ; NCT02820454). Il s’agit d’une étude monocentrique, ouverte, évaluant la faisabilité et la tolérance d'AGuIX® associé à une irradiation panencéphalique (30 Gy, 10 Fr de 3 Gy) pour des patients atteints de métastases cérébrales multiples. L'objectif principal est de déterminer la dose maximale tolérée des nanoparticules avec un schéma d’escalade de dose par palier de 3 patients à 15, 30, 50, 75 et 100 mg/kg. Les objectifs secondaires sont l’étude pharmacocinétique de la distribution d'AGuIX® par IRM, de la survie sans progression intracrânienne et de la survie globale. La première administration chez l’homme a été réalisée au CHU de Grenoble le 18 juillet 2016 et le dernier patient (n=15) a été inclus le 06 février 2018. L’ensemble des lésions, quelques soit l’origine histologique (poumon, mélanome, sein) ont eu une prise de contraste d’AGuIX® dont la concentration retrouvée dans la tumeur était proportionnelle à la dose injectée. La demi-vie sanguine moyenne est de 1h09 (± 26min). La tolérance au traitement a été bonne avec une escalade de dose jusqu’à 100 mg/kg qui devient ainsi la dose retenue pour la suite des essais cliniques. Sur les 14 patients évaluables, 12 ont eu un bénéfice clinique du traitement avec une diminution du volume tumoral. Les résultats préliminaires sont prometteurs en termes de tolérance, de distribution et d’efficacité et devront être confirmés par l’étude de phase 2 multicentrique randomisée prévue pour la fin de l’année 2018.The occurrence of multiple brain metastases is a critical evolution of many cancers with a major impact on overall survival. A new gadolinium-based nanoparticle, AGuIX®, has recently demonstrated its efficacy as a radiosensitizer and MRI contrast agent in several preclinical studies. The objective of this thesis is to establish a proof of concept on an animal model and then to perform the first administration of this new drug in humans in a phase 1 trial. The first part of this work consisted of a 6 MeV irradiation after AGuIX® injection of a Fisher rat model carrying 9L cerebral gliomas assessed by MRI. A favorable distribution of nanoparticles was observed by EPR effect (Enhanced Permeability and Retention) with a concentration of gadolinium into the tumor 20 times higher than in healthy brain. The radiosensitizing effect was demonstrated with a significant decrease in tumor size (p=0.02) for the irradiated group with AGuIX® injection. These results, combined with the favorable safety profile in animal models, motivated the transfer of this new drug to humans in a Phase 1 study named NANO-RAD (EudraCT2015-004259-30; NCT02820454). This is a monocentric, open-label study evaluating the feasibility and safety of AGuIX® combined with whole brain radiation therapy (30 Gy, 10 Fr of 3 Gy) for patients with multiple brain metastases. The main objective is to determine the maximum tolerated dose of nanoparticles with a dose escalation scheme by steps of 3 patients at 15, 30, 50, 75 and 100 mg/kg. Secondary objectives are the pharmacokinetics, distribution of AGuIX® by MRI, intracranial progression-free survival and overall survival. The first human administration was performed at Grenoble University Hospital on 18 July 2016 and the last patient (n=15) was included on 06 February 2018. All metastases, whatever the histological type (lung, melanoma, breast) had a uptake of AGuIX® whose concentration in the tumor was proportional to the injected dose. The average blood half-life is 1h09 (± 26 min). Tolerance to the treatment was good with a dose escalation up to 100 mg/kg, which became the dose selected for further clinical trials. Of the 14 evaluable patients, 12 had a clinical benefit of treatment with a decrease in tumor volume. These preliminary results are promising in terms of safety, distribution and efficacy and should be confirmed by the randomized multicenter Phase 2 study planned for the end of 2018

Traitement des métastases cérébrales par radiothérapie et nanoparticule de gadolinium : du modèle pré clinique à l'utilisation chez l'homme

The occurrence of multiple brain metastases is a critical evolution of many cancers with a major impact on overall survival. A new gadolinium-based nanoparticle, AGuIX®, has recently demonstrated its efficacy as a radiosensitizer and MRI contrast agent in several preclinical studies. The objective of this thesis is to establish a proof of concept on an animal model and then to perform the first administration of this new drug in humans in a phase 1 trial. The first part of this work consisted of a 6 MeV irradiation after AGuIX® injection of a Fisher rat model carrying 9L cerebral gliomas assessed by MRI. A favorable distribution of nanoparticles was observed by EPR effect (Enhanced Permeability and Retention) with a concentration of gadolinium into the tumor 20 times higher than in healthy brain. The radiosensitizing effect was demonstrated with a significant decrease in tumor size (p=0.02) for the irradiated group with AGuIX® injection. These results, combined with the favorable safety profile in animal models, motivated the transfer of this new drug to humans in a Phase 1 study named NANO-RAD (EudraCT2015-004259-30; NCT02820454). This is a monocentric, open-label study evaluating the feasibility and safety of AGuIX® combined with whole brain radiation therapy (30 Gy, 10 Fr of 3 Gy) for patients with multiple brain metastases. The main objective is to determine the maximum tolerated dose of nanoparticles with a dose escalation scheme by steps of 3 patients at 15, 30, 50, 75 and 100 mg/kg. Secondary objectives are the pharmacokinetics, distribution of AGuIX® by MRI, intracranial progression-free survival and overall survival. The first human administration was performed at Grenoble University Hospital on 18 July 2016 and the last patient (n=15) was included on 06 February 2018. All metastases, whatever the histological type (lung, melanoma, breast) had a uptake of AGuIX® whose concentration in the tumor was proportional to the injected dose. The average blood half-life is 1h09 (± 26 min). Tolerance to the treatment was good with a dose escalation up to 100 mg/kg, which became the dose selected for further clinical trials. Of the 14 evaluable patients, 12 had a clinical benefit of treatment with a decrease in tumor volume. These preliminary results are promising in terms of safety, distribution and efficacy and should be confirmed by the randomized multicenter Phase 2 study planned for the end of 2018.L'apparition de métastases cérébrales multiples est une évolution critique de nombreux cancers avec un impact majeur sur la survie globale. Une nouvelle nanoparticule à base de gadolinium, l’AGuIX®, a récemment démontré son efficacité en tant que radiosensibilisant et agent de contraste IRM dans plusieurs études précliniques. L’objectif de cette thèse est d’établir une preuve de concept sur un modèle animal puis de réaliser la première administration chez l’homme de ce nouveau médicament dans le cadre d’un essai de phase 1.La première partie de ce travail a consisté à l’irradiation en 6 MeV après injection d’AGuIX® d’un modèle de rat Fisher porteur du gliome cérébral 9L suivi par IRM. Nous avons mis en évidence une distribution favorable des nanoparticules dans la tumeur par effet EPR (Enhanced Permeability and Retention) avec une concentration de gadolinium dans la tumeur 20 fois plus importante que dans le cerveau sain. L’effet radiosensibilisant a été démontré avec une diminution significative (p=0.02) de la taille des tumeurs dans le groupe irradié après injection d’AGuIX®. Ces résultats, associés au profil de tolérance favorable sur les modèles animaux ont motivés le transfert chez l’homme de ce nouveau médicament dans une étude de phase 1 nommée NANO-RAD (EudraCT 2015-004259-30 ; NCT02820454). Il s’agit d’une étude monocentrique, ouverte, évaluant la faisabilité et la tolérance d'AGuIX® associé à une irradiation panencéphalique (30 Gy, 10 Fr de 3 Gy) pour des patients atteints de métastases cérébrales multiples. L'objectif principal est de déterminer la dose maximale tolérée des nanoparticules avec un schéma d’escalade de dose par palier de 3 patients à 15, 30, 50, 75 et 100 mg/kg. Les objectifs secondaires sont l’étude pharmacocinétique de la distribution d'AGuIX® par IRM, de la survie sans progression intracrânienne et de la survie globale. La première administration chez l’homme a été réalisée au CHU de Grenoble le 18 juillet 2016 et le dernier patient (n=15) a été inclus le 06 février 2018. L’ensemble des lésions, quelques soit l’origine histologique (poumon, mélanome, sein) ont eu une prise de contraste d’AGuIX® dont la concentration retrouvée dans la tumeur était proportionnelle à la dose injectée. La demi-vie sanguine moyenne est de 1h09 (± 26min). La tolérance au traitement a été bonne avec une escalade de dose jusqu’à 100 mg/kg qui devient ainsi la dose retenue pour la suite des essais cliniques. Sur les 14 patients évaluables, 12 ont eu un bénéfice clinique du traitement avec une diminution du volume tumoral. Les résultats préliminaires sont prometteurs en termes de tolérance, de distribution et d’efficacité et devront être confirmés par l’étude de phase 2 multicentrique randomisée prévue pour la fin de l’année 2018

Treatment of brain metastases using gadolinium nanoparticles: NANORAD first in man study

International audienceThe occurrence of multiple brain metastases is a critical evolution of many cancers with a major impact on overall survival. A new gadolinium-based nanoparticle, AGuIX®, has recently demonstrated its efficacy as a radiosensitizer and MRI contrast agent in several preclinical studies. The objective of this research is to establish a proof of concept on an animal model and then to perform the first intravenous administration of this new drug in humans in a phase 1 trial.The first part of this work consisted of a 6 MeV irradiation after AGuIX® injection of a Fisher rat model carrying 9L cerebral gliomas assessed by MRI. A favorable distribution of nanoparticles was observed by EPR effect (Enhanced Permeability and Retention) with a concentration of gadolinium into the tumor 20 times higher than in healthy brain. The radiosensitizing effect was demonstrated with a significant decrease in tumor size (p=0.02) for the irradiated group with AGuIX® injection. These results, combined with the favorable safety profile in animal models, motivated the transfer of this new drug to humans in a Phase 1 study named NANO-RAD (EudraCT2015-004259-30; NCT02820454).This is a monocentric, open-label study evaluating the feasibility and safety of intra venous AGuIX® combined with whole brain radiation therapy (30 Gy, 10 Fr of 3 Gy) for patients with multiple brain metastases. The main objective is to determine the maximum tolerated dose of nanoparticles with a dose escalation scheme by steps of 3 patients at 15, 30, 50, 75 and 100 mg/kg. Secondary objectives are the pharmacokinetics, distribution of AGuIX® by MRI, intracranial progression-free survival and overall survival.The first human administration was performed at Grenoble University Hospital on 18 July 2016 and the last patient (n=15) was included on 06 February 2018. All metastases, whatever the histological type (lung, melanoma, breast) had a uptake of AGuIX® whose concentration in the tumor was proportional to the injected dose. The average blood half-life is 1h09 (± 26 min). Tolerance to the treatment was good with a dose escalation up to 100 mg/kg, which became the dose selected for further clinical trials. Of the 14 evaluable patients, 12 had a clinical benefit of treatment with a decrease in tumor volume.These preliminary results are promising in terms of safety, distribution and efficacy and should be confirmed by the randomized multicenter Phase 2 study started in March 2019

EPR-mediated tumor targeting using ultrasmall-hybrid nanoparticles: From animal to human with theranostic AGuIX nanoparticles

International audienceInterest of tumor targeting through EPR effect is still controversial due to intrinsic low targeting efficacy and rare translation to human cancers. Moreover, due to different reasons, it has generally been described for relatively large nanoparticles (NPs) (hydrodynamic diameter > 10 nm). In this review EPR effect will be discussed for ultrasmall NPs using the example of the AGuIX® NP (Activation and Guiding of Irradiation by X-ray) recently translated in clinic. AGuIX® NP is a 4 ± 2 nm hydrodynamic diameter polysiloxane based NP. Since AGuIX® NP biodistribution is monitored by magnetic resonance imaging (MRI) and its activation is triggered by irradiation upon X-rays, this NP is well adapted for a theranostic approach of radiotherapy cancer treatment. Here we show that AGuIX® NP is particularly well suited to benefit from EPR-mediated tumor targeting thanks to an ultrasmall size and efficacy under irradiation at small dose. Indeed, intravenously-injected AGuIX® NP into rodent cancer models passively reached the tumor and revealed no toxicity, favoured by renal clearance. Moreover, translation of AGuIX® NP accumulation and retention into humans carrying brain metastases was validated during a first-in-man phase Ib trial taking advantage of easy biodistribution monitoring by MRI

Gadolinium-Based Nanoparticles and Radiation Therapy for Multiple Brain Melanoma Metastases and brain tumors: from bench to beside.

International audienceMore than half of all clinical cancer patients undergo radiation therapy. Besides the poor prognosis for multiple brain metastases and brain tumors, the delivery of curative radiation dose to induce tumor-kill is strongly restricted by the healthy proximal brain. We describe a nanoparticle which can act as MR contrast agent and radiosensitizer concomitantly, for the detection, monitoring and treatment of brain cancers

Gadolinium-Based Nanoparticles AGuIX and Radiation Therapy for Multiple Brain Melanoma Metastases and Brain Tumors: From Bench to Bedside

National audienceMore than half of all clinical cancer patients undergo radiation therapy. Besides the poor prognosis for multiple brain metastases and brain tumors, the delivery of curative radiation dose to eradicate tumor is strongly restricted by the healthy proximal brain. We describe a nanoparticle which can act as MR contrast agent and radiosensitizer concomitantly, for the detection, monitoring and treatment of brain cancers.Biodistribution, toxicity and pharmacokinetic studies were carried out in rodents and cynomolgus monkeys to demonstrate the safety of the nanoparticles after intravenous injection. The MR imaging properties of the nanoparticles were used to monitor their tumor accumulation in rodent bearing brain tumors. In vitro and in vivo efficacy of the nanoparticles was evaluated in rodent bearing brain tumors.The regulatory toxicity investigations demonstrated the absence of any ante- or post-mortem finding in rodent and nonhuman primates after repeated administration of nanoparticles; thus, the no-observed-effect level (NOEL) was determined and a human equivalent dose of 120 mg/kg was defined. In rodents, MR imaging indicated the renal elimination of the nanoparticles and their passive accumulation in the tumor region for several hours. The combination of nanoparticles and irradiation created significant dose enhancement in vitro, and improved the survival of rodent bearing aggressive brain tumor.The therapeutic efficacy of AGuIX has been demonstrated in aggressive pathologies, i.e. multiple brain metastases and brain tumors. In addition, the nanoparticles possess natural T1-MRI contrast agent properties, conferring a dual-property for image-guided radiation therapy. The data in rodents and nonhuman primates clearly demonstrates and justifies their clinical translational potential. The upcoming first-in-man clinical trial will investigated both imaging and radiation therapy improvement for advanced precision medicine

Doses delivered by portal imaging quality assurance in routine practice of adjuvant breast radiotherapy worth to by monitored and compensated in some cases

International audienceBackground: Imaging, in radiotherapy, has become a routine tool for repositioning of the target volume at each session. The repositioning precision, currently infracentimetric, evolves along with the irradiation techniques. This retrospective study aimed to identify practices and doses resulting from the use of high energy planar imaging (portal imaging) in daily practice. Methods: A retrospective survey of portal images (PIs) was carried out over 10 years for 2,403 patients and for three linacs (1 Elekta SLi, 2 Varian Clinac) for postoperative mammary irradiations. Images were taken using a standardized number of monitor units (MU) for all patients. Due to the variable sensitivities of the detectors and the possibility of adjustment of the detector-patient distance, the number of MU were 3; 2 and 1 respectively, for Elekta SLi ® , Clinac 600 ® and Clinac 2100 ®. Then, a representative cumulated dose was calculated in simplified reference conditions (5 cm depth, beam of 10 cm × 10 cm, 6 MV), considering the total number of images taken during the whole treatment course. The consistency between the representative doses and the actual absorbed doses received by the patients was verified by simulating a series of typical cases with the treatment plan dose calculation system. Results: The delivered doses differ significantly between the three linacs. The mean representative dose values by complete treatment were 0.695; 0.241 and 0.216 Gy, respectively, for SLi, Clinac 600 and Clinac 2100. However, 15 patients were exposed to a dose >2 Gy with a maximum dose of 5.05 Gy. The simulated doses were very similar to the representative doses. Conclusions: A significant dose delivery was highlighted by this study. These representative doses are presently communicated weekly to the radiation oncologist for the radiation protection of their patients. Moreover, they should be taken into account in a possible study of long-term stochastic risks

External evaluation of the Briganti nomogram to predict lymph node metastases in intermediate-risk prostate cancer patients

International audiencePurpose: The Briganti nomogram can be used with a threshold of 5% to decide when to offer lymph node dissection during radical prostatectomy. The objective of the study was to assess the accuracy of the Briganti nomogram on intermediate-risk prostate cancer patients managed in a single academic department. Methods: We retrospectively reviewed the files of all patients managed by radical prostatectomy (RP) and bilateral pelvic lymph node dissection (BPLND) in our center between 2005 and 2017. The overall accuracy of the model in predicting metastatic lymph node disease was quantified by the construction of a receiver-operator characteristic (ROC) curve. A calibration plot was drawn to represent the relationship between the predicted and observed frequencies.Results: We included 285 patients, among whom 175 (61.4%) were classified as intermediate risk as defined by D’Amico. The median follow-up was 60 (34-93) months. Twenty-seven patients (9.5%) were diagnosed with lymph node metastases. The median number of lymph nodes removed was 10 (7-14). The mean Briganti score was 19.3% in patients with lymph node involvement (LNI) and 6.3% in patients without LNI. Focusing on intermediate-risk patients, 91(52%) and 84 (48%) had a Briganti score <5% and 5%, respectively, among whom 6 (6.6%) and 7(8.3%) had lymph node metastases. The accuracy of the score was low for intermediate risk patients with an area under the curve (AUC) of 53.1% (95% CI 0.45-0.61). Conclusion: The Briganti nomogram in our retrospective cohort showed low accuracy for the prediction of lymph node involvement in an intermediate-risk prostate cancer population

Unexpected Benefits of Multiport Synchrotron Microbeam Radiation Therapy for Brain Tumors

International audienceDelivery of high-radiation doses to brain tumors via multiple arrays of synchrotron X-ray microbeams permits huge therapeutic advantages. Brain tumor (9LGS)-bearing and normal rats were irradiated using a conventional, homogeneous Broad Beam (BB), or Microbeam Radiation Therapy (MRT), then studied by behavioral tests, MRI, and histopathology. A valley dose of 10 Gy deposited between microbeams, delivered by a single port, improved tumor control and median survival time of tumor-bearing rats better than a BB isodose. An increased number of ports and an accumulated valley dose maintained at 10 Gy delayed tumor growth and improved survival. Histopathologically, cell death, vascular damage, and inflammatory response increased in tumors. At identical valley isodose, each additional MRT port extended survival, resulting in an exponential correlation between port numbers and animal lifespan (r2 = 0.9928). A 10 Gy valley dose, in MRT mode, delivered through 5 ports, achieved the same survival as a 25 Gy BB irradiation because of tumor dose hot spots created by intersecting microbeams. Conversely, normal tissue damage remained minimal in all the single converging extratumoral arrays. Multiport MRT reached exceptional ~2.5-fold biological equivalent tumor doses. The unique normal tissue sparing and therapeutic index are eminent prerequisites for clinical translation