Cancer is rapidly becoming the most frequent cause of morbidity and mortality in the EU, accounting for a quarter of all deaths in EU. Without breakthroughs in treatment, cancer is likely to remain one of the biggest killers in the 21st century. Immunotherapy of cancer by checkpoint inhibitors, vaccines or adoptive T cell therapy is coming of age and has the potential to cure cancer, but is still hampered by some major limitations. For instance, Adoptive Cell Therapy (ACT) with unmanipulated or engineered T cells (TCR-transgenic and CAR-T cells) has indeed demonstrated success in the treatment of patients affected by leukemias, but is much less effective against lymphomas and solid tumors. One likely explanation is that we do not educate the right type of anti-tumor T cells. The T cells considered to be the gold standard for tumor therapy have stem cell memory features, but the proper and safe way to generate these fit T cells for clinical purposes is still an unresolved matter. Here we propose an advanced transformative technology termed INCITE, utilizing a novel high-resolution 3D microfabrication technology to engineer a specially tailored microenvironment that will be inhabited by cells central for T cells education in order to generate the fittest anti-tumor T cells for advanced adoptive T cell therapy. INCITE will bring together a transdisciplinary consortium capable of developing this innovative platform by combining state-of-the-art 3D printing, computer modeling, bioengineering, bioinformatics, immunology, developmental and cancer biology approaches, toward the development of a functional immune niche for selection and expansion of tumor-rejecting T cells. The INCITE platform will revolutionize the treatment of cancer patients with ACT, with a profound impact on the quality of life and well-being of millions of people.

Lymphedema is a disabling condition induced by the accumulation of fluid and fat in the arm or in the leg. It is an untreatable disease that affects 4 millions people in Europe and more than 120 millions people worldwide. It is handicapping, painful and impacts substantially the quality of life. In western countries, lymphedema is generally a consequence of cancer treatments i.e. ten to fifteen percent of women will develop lymphedema after breast cancer. The main objective of Theralymph will be to establish a non-integrative gene therapy for this unmet medical need. The theralymph translational research program brings together bench scientists from 5 European countries and physicians from the hosted Rangueil hospital in which the PI institute is located to perform a Phase I/II trial focusing on women who developed lymphedema after breast cancer. Based on decades of disappointing results of monotherapy-gene delivery in cardiovascular diseases, our approach will be based on multiple gene therapy targeting both superficial lymphatic endothelium and deeper lymphatic collectors. We will identify molecules that possess a synergistic effect with the established lymphangiogenic factor VEGFC. Theralymph project will determine risk factors for lymphedema and cartography the lymphatic network in the pathology. It will decipher whether lymphatic intrinsic molecules or microenvironmental peptides or lipids are modified in the lymphedematous arm to promote the lymphatic dysfunction. Theralymph will validate the best molecule combination that restores the lymphatic drainage in in preclinical lymphedema models before human study. The Phase I/II gene therapy clinical trial will be performed in the vascular medicine department of Toulouse’s hospital, where the PI laboratory is located. This trial will use an innovative technology based on recently developed non-integrative lentiflash lentiviral vectors that allow a transient and highly efficient in vivo gene delivery.