Recent progress has been made in advanced melanoma with drug targeting immune system such as ipilimumab targeting CTLA-4 and nivolumab targeting PD-1. Some case reports and preclinical data suggested that the antitumoral immune response of these immune check point inhibitors (ipilimumab and nivolumab as well) could be enhanced if associated with massive tumoral antigen release in the blood stream, due to local treatment such as high dose radiotherapy (HR). The first rigorous scientific demonstration of this phenomenon was done by Demaria et al. They showed that irradiation of xenograft tumor could induce decrease of tumoral growth of a non-irradiated other xenograt tumor. This effect was due to immune response to irradiation but it only occured when immune system was modulated by CTLA-4 inhibition. In that experiences CTLA4 and radiation actions were synergistic.~Dovedi et al. also reported that targeting PD-1/PD-L1 pathway have greater anti-tumor efficacy if concomitant radiotherapy was given and especially if radiotherapy was multifractionated.~Very interestingly the fractionated radiotherapy also induced huge increase of tumoral PD-L1 expression by three times 5 days after beginning of radiotherapy. This could explain the synergistic impact of this strategy.~At least eight clinical studies are ongoing, testing the combination of CTLA-4 blockade with radiotherapy in metastatic melanoma or other tumors, with various treatment schedules either for ipilimumab (3 or 10 mg/kg) or radiotherapy (before or after ipilimumab, fractions of 6 to 8 Gy; total body irradiation or treatment of only one metastasis).~One study (NCT01565837) is a phase II study that analyses the efficacy of 10mg/kg ipilimumab (every 3 weeks) associated with HR for all metastatic sites but only for oligometastatic patients (< 6 metastasis), which reflects only a minority of metastatic melanoma patients.~Such strategy is of high interest because it takes into account the putative tumoral heterogeneity which could lead to failure of the association of nivolumab with the irradiation of only one tumor site.~The investigators propose to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).They have chosen 3 fractions instead of only 1 for each tumor site because of preclinical data in mice showing that one fraction is less efficient than several fractions to stimulate the immune system and kill tumoral cells. The increase of the number of fractions could also lead to an increase of the diversity of tumoral antigens released in the blood stream which could also favors diversity of the T-cell receptor repertoire of intratumoral T cells.~In our protocol dose constraint for each tissue type can be easily achieved with the 3 X 6 Gy schedule without excess of toxicity.~In conclusion the present protocol aims to increase the quantity and diversity of released tumoral antigens by providing multisite, multifractionated HR during nivolumab treatment in advanced untreated melanoma patients.~The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.
Combining nivolumab with conventional multisite high dose radiotherapy seems to be an interesting approach that could increase the antitumoral effect of nivolumab by increasing the diversity and quantity of tumoral antigen presentation thanks to radiotherapy. Multifractionated high dose radiotherapy (HR) targeting various tumor sites could also increase occurrence of tumor mutations and the diversity of the T-cell receptor repertoire of intratumoral T cells.~The purpose of this study is to combine nivolumab with 3 fractions of HR of one metastasis for each tumor site (defined as skin/muscle, thoracic, abdomen, bone, other).~The investigators hypothesize that combining nivolumab with multisite, multifractionated HR increases the overall survival rate at 1 year compared to published data with nivolumab alone.