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.

Breast cancer (BC) is a complex disease with high prevalence in the EU. 75% of the tumors are estrogen receptor-positive (ER+), and are treated with endocrine therapies (ET). MESI-STRAT will develop new concepts for knowledge-based stratification of patients into subgroups with different ET resistance mechanisms. We will establish predictive models for (1) patient stratification prior and during ET; (2) recurrence risk assessment when ending ET; (3) marker panel development to guide targeted therapies for ET-resistant patients; (4) novel ET resistance mechanism-based therapy design. The unique collection of matched BC tissue, serum, and >10 years follow-up from the patient organization PATH is essential for the longitudinal analysis of ET resistance and relapse. Our team of oncologists, modelers, bioinformaticians and experimentalists will develop new computational models in combination with network analyses and pharmacogenomics, to integrate multi-omics data and explore metabolic and signaling (MESI) networks driving ET resistance. Metabolite marker panels measured in biological fluids will enable patient stratification, resistance monitoring and clinical decision-making. This is a new concept as BC metabolism is poorly explored for diagnostics and therapy. Upon successful validation in preclinical models, the predictive marker panels and related treatments will be jointly investigated by our clinical and industrial partners in clinical studies. Our 3 SMEs will closely co-develop the research, and directly exploit the MESI-STRAT results. BC accounts for the highest cancer-related health-care costs in the EU. Our stratification concepts will increase cost effectiveness and the patients’ quality of life by (1) avoiding ineffective therapies, (2) marker detection in body fluids without surgical interventions, and (3) reducing clinical trial cohorts by improved stratification. This will accelerate the translation of MESI-STRAT results into medical use.