Clinical transfer of AGuIX®-based radiation treatments for locally advanced cervical cancer: MR quantification and in vitro insights in the NANOCOL clinical trial framework

Theragnostic Gadolinium-Based Nanoparticles Safely Augment X-ray Radiation Effects in Patients with Cervical Cancer

“…As recently published, such data may be important to guide the optimal radiotherapy dose when radiosensitizing agents such as AGuIX nanoparticles are coadministered, taking into account a specific radio-enhancement factor for each patient in order to avoid unexpected side effects, such as those observed in this study. 2 One may speculate that the two patients presenting atypical local reactions after irradiation illustrate the consequences of focal relative over-radiation dosage that may be attributed to the combination of AGuIX and radiotherapy, underscoring the need to use our theragnostic quantification workflow to precisely master the absorbed dose by adjusting the radiotherapy prescription to a voxel-based quantification. 2 In the context of a radiosensitizing agent, further clinical developments may include quantification as a major perspective to increase personalization of treatment (e.g., refinement of radiotherapy dose prescription) in order to minimize the risk of severe complications in irradiated volumes while still increasing tumor control rates.…”

“…2 One may speculate that the two patients presenting atypical local reactions after irradiation illustrate the consequences of focal relative over-radiation dosage that may be attributed to the combination of AGuIX and radiotherapy, underscoring the need to use our theragnostic quantification workflow to precisely master the absorbed dose by adjusting the radiotherapy prescription to a voxel-based quantification. 2 In the context of a radiosensitizing agent, further clinical developments may include quantification as a major perspective to increase personalization of treatment (e.g., refinement of radiotherapy dose prescription) in order to minimize the risk of severe complications in irradiated volumes while still increasing tumor control rates. Here, the only significant side effect occurring in irradiated volumes was observed at the level of the cervix (where the tumor was seated and exposed to very high radiotherapy doses).…”

“…Importantly, in vitro evaluations have demonstrated that the radio-sensitizing activity of AGuIX nanoparticles enhanced radiation effects with a ratio ranging from 1.1 to 2.5, depending on the energy of photon beams and including radioresistant tumor cell lines. ,, In vitro and in vivo preclinical data showed that the therapeutic effect of AGuIX nanoparticles mostly relies on a focal increase in radiation dose deposits, translating into an increase of complex DNA damage within tumor cells . Recent preclinical models suggested an effect of AGuIX on the tumor ability to repair DNA damage by homologous recombination and on its capacity of induction of apoptosis and cell cycle arrest. , Other data suggest an immunomodulatory effect, with induction of immunogenic death in irradiated tumor cells and activation of a systemic T response …”

“…Administration of AGuIX nanoparticles may, in the long run, be also used to potentially decrease radiotherapy doses while maintaining an antitumor effect, taking into account recent preclinical data, showing a dose enhancement factor of about 15% at 2 Gy for tumors. 2 Some aspects of this approach deserve particular attention and justify step-by-step evaluation. Indeed, we observed two cases of unusual reactions in patients having radiological modifications of the cervix, including one symptomatic cervical necrosis.…”

“…AGuIX in a patient biopsy was observed by NanoSIMS (Curie Institute, Orsay France) by superimposing the image of the tissue structure obtained from the 12 C 14 N − signal with those of the nanoparticles represented by the 28 Si − signal since AGuIX are made of polysiloxane, as described in a previous study. 2 A multiplex quantification was performed for H 2 AX foci per tumor cell and for the following immune cells: T cells (CD3), macrophages (CD68), B lymphocytes (CD20), natural killers (CD57) and tumorinfiltrating lymphocytes (TILs). As there was no control arm in this study, an indirect comparison of immune cell infiltrates was performed with samples from patients treated with chemoradiation and brachytherapy in another protocol.…”