The standard medical-and-surgical treatment of ovarian carcinoma patients relies on a systemic chemotherapy (carboplatin-paclitaxel), a tumor debulking surgery meant to be complete (no post-operative residual lesion), and a subsequent maintenance treatment with modern targeted agents. Recent studies identified a patient population (~14,000 patients / year in Europe), whose prognostic is poor (5 year-overall survival (OS) <20%) due to a refractory cancer, characterized by a poor chemosensitivity (assessable online with the numeric CA-125 KELIMTM score <1.0), and by a disease found non-resectable disease after 3-4 cycles of chemotherapy. In these patients, there is a high uncertainty about the best treatment adjustments to apply. SALVOVAR is a European project led by HCL, meant 1) to raise the physician awareness, and propose practical and affordable diagnostic tools for identifying these patients, and 2) to assess the utility (OS benefit), acceptability (quality-of-life; patient perception) and affordability (cost-effectiveness, including country coverage policies) of solutions based on adjustments of their medical-and-surgical treatment. These solutions implementable in routine may improve their prognosis, according to recent literature data. The project will be based on a large pragmatic randomized phase III trial, sponsored by ARCAGY-GINECO group, and activated in 6 countries (ENGOT network; ~100 recruiting centers), with the objective of demonstrating an OS benefit with the chemotherapy densification (weekly carboplatine-paclitaxel dose-dense regimen) compared to the continuation of the standard 3-weekly regimen. Total 685 patients treated with the standard neo-adjuvant chemotherapy will be pre-screened to randomize 240 patients. Dissemination, and communication will be carried-on to ensure the quality of the project, and inform the stakeholders, patients, public, health authorities/ payers of the project outcomes, mean to change the practices. This action is part of the Cancer Mission cluster of projects on ‘Diagnosis and treatment’.

Langerhans Cell Histiocytosis (LCH) is a rare disease that mostly affects children but can be present at any age in life. The disease is characterized by an accumulation of mononuclear phagocytes, associated with a dense inflammatory infiltrate. A mutation of the MAP kinase pathway is systematically found in LCH lesions and in hematopoietic progenitors, the most common being the BRAFV600E mutation. The coordinator of this grant has recently demonstrated in a mouse model that mutated mononuclear phagocytes exhibit a senescence program, which explains the very peculiar pathophysiology of this disease. The aims of this project are 1) to confirm the presence of this senescence program in the bone marrow hematopoietic progenitors of LCH patients, in order to formally confirm its major implication in LCH pathophysiology; then 2) to test different senolytic drugs, taking advantage of our mouse model. Finally, the last objective of this project is 3) to dissect the LCH-neurodegenerative syndrome, paving the way to new treatments. The association of access to human samples and LCH mouse models will help to define new therapeutic strategies in order to propose new treatments to refractory LCH patients. Moreover the coordinator of this grant has an important expertise in LCH as she developed the mouse model and in parallel follow-up patients with LCH.

The PragmaTIL trial aims to optimize treatment of cancer patients with Tumour-Infiltrating Lymphocytes Adoptive Cell Therapy (TIL-ACT) and substantially expand and improve the clinical implementation of this treatment modality in academic hospitals. To this end, treatment related toxicities, associated to high-dose interleukin 2 (HD-IL-2) required for expansion and activation of TILs will be reduced while maintaining efficacy. This improved tolerability will achieve a better clinical management of patients and enhance their quality of life, both of which represent major barriers for applying this treatment. The objectives of PragmaTIL are: i) To determine whether TIL-ACT using IL-2 analog ANV419 reduces the frequency of Grade 2-4 study-related non-hematological toxicities; ii) To compare the quality of life (QoL) of patients during their hospitalization period, using ANV419 vs HD-IL-2. Also, to compare short and long-term measurements of treatment-related toxicities and QoL co-defined by and for patients and their caregivers; and iii) To develop the health technology assessment (HTA) of TIL-ACT using ANV419, as well as a social return of investment (SROI) analysis. To achieve these objectives, the PragmaTIL project is structured into 6 WP that cover all the requirements to implement the project: WP1) Clinical Trial; WP2) IMPD Coordination, RA and Pharmacovigilance; WP3) Patients as co-researchers and Evaluation of Short- and Long-term PROs; WP4) Health Economics; WP5) SROI, Sustainability and Exploitation; WP6) Scientific Coordination, Project Management, Communication and Dissemination. The global impact of this project will not only reach patients, clinical and translational researchers and policy makers but may help to achieve a better acceptance of these therapies by society at large. This action is part of the Cancer Mission cluster of projects on "Diagnosis and treatment".