Adoptive cell therapy (ACT) recently became an important treatment modality for cancer . Since 2017, several chimeric antigen receptor (CAR)-T cell therapies approved by the FDA/EMA and more are expected to receive approval for clinical use. Currently, more than 250 clinical ACT trials are ongoing. Already in 2021, the market size was >$1 billion and is expected to grow tremendously to >$25 billion by 2030. ACT products require extensive ex vivo manipulation and expansion of patient derived T cells prior to reinfusion back into patients to attack cancer cells. Unfortunately, T cell exhaustion and loss of function after reinfusion form a major problem in currently used ex vivo expansion protocols. The solution. Dedicated tuning of T cells during ex vivo expansion to preserve their anti- cancer function and prevent exhaustion. In the body, T cells are activated by antigen presenting cells (APC) to initiate an immune response. As patient-derived APC are often immunosuppressed, much effort is spent on developing 'artificial antigen presenting cells' (aAPC) to expand immune cells for ACT. We developed a unique polymeric aAPC platform, termed immunofilaments, that provide a highly flexible-, scalable-, GMP compliant- and affordable- solution for robust production of T cells for ACT. Our initial findings indeed indicate that we can diminish T cell exhaustion and outcompete products currently used in the clinic for ex vivo T cell expansion. Tune-IT will validate the technical and commercial feasibility of this novel technology platform that exploits immunofilaments to significantly improve function and longevity of ACT products in patients. In Tune-IT, we will: 1) demonstrate that tuning of ex vivo cultured therapeutic T cells will prevent exhaustion and loss of tumor killing capacity after reinfusing T cells and 2) perform market and business case analyses to ensure commercial feasibility and market entry through Simmunext Biotherapeutics, a Radboudumc spin-off

Deriving mammalian retina from stem cells has had a large impact on the study of the biology of vision and is called organoid. Compared to in vivo retina, retinal organoids are far less functionally sophisticated in terms of their synapses, connectivity, discrimination between different light stimuli and their electrical action potentials. This project will overcome this functional constraint of retinal organoids by studying electrophysiological events-derived functional maturation of mouse retina during retinal development and then stimulating those events with the help of mathematical models in order to induce the same functionality in mouse and human retinal organoids. NeuFRO will achieve a resonance in the field by generating retinal organoids with the neuronal connectivity and the natural diversity of functions using interdisciplinary fields including electrophysiology, developmental biology, and computationally-derived electrical stimulation. Initially, I will create a holistic roadmap of the electrical features of immature mouse retina during development that shows self-organization through electrophysiology. With milli- to nanometer imaging precision, electrical activities derived the circuit formation will be spatiotemporally documented. Then I will decode this space-time code of intrinsic electrical patterns and neuronal connectivity using an ambitious strategy incorporating Hodgkin-Huxley and linear-nonlinear models. Next, such electrical response models will be applied to immature retinal organoids (mouse and human) by an innovative ‘sandwich’ electrophysiology technique during the development in vitro. With this approach, I will induce naturalistic electrical features in the retinal organoid, allowing the functional neurons to wire and fire appropriately into retinal organoids, particularly visual circuits. This ground-breaking approach will advance techniques for generating functional human retina.

The evaluation of new medicines for rare diseases (RD) including rare paediatric RDs is challenging for several reasons, among which are the small patient sample sizes, heterogeneity of patients and diseases and heterogeneity in disease knowledge. Due to these difficulties, access to effective treatments and the number of treatment options are often limited in RDs. INVENTS aims to provide clinical trial trialists, researchers and regulators with a global framework encompassing methods, workflows and evidence assessment tools to be implemented in orphan and paediatric drug development. Our ambition is to significantly improve the evaluation of evidence and regulatory decision-making through the development and validation of: refined longitudinal model-based diseases trajectories and treatment effect, improved extrapolation models, in silico trials (e.g., virtual patient cohorts), optimised model-based clinical trial designs and evidence synthesis methods. These will be evaluated through simulation studies and tested on extensive data from a range of use cases provided by our industrial partners Roche and Novartis and Real World data (RWD) from RD registry. The INVENTS framework will improve consistency and efficiency of the drug evaluation process for RD by augmenting clinical evidence without compromising its scientific integrity and providing regulators assessment credibility criteria. At the end of this 5 years project, the European industry will be able to exploit novel and improved clinical trial designs, in silico trials and RWD analysis approaches supporting drug development in RD. The European Medicine Agency and European national regulators (including Health Technology Assessment bodies) will be supplied with a general framework allowing better informed decision-making. Most importantly, RD patients will benefit from an increased and faster access to efficacious and safe treatments.

Transplantation of autologous split-thickness skin -the epidermis with a tiny layer of dermis- remains the golden standard for various skin wounds like burns and large trauma. This treatment, however, comes with a number of serious drawbacks, including pain, mobility-limiting contractures and disfiguring scars. The SkinTERM consortium will address wound healing in a completely different way, recapitulating (certain aspects of) skin embryonic development in adults, and aiming for regeneration rather than repair. Skin organogenesis will be induced by key elements taken from the extracellular matrix of foetal and non-scarring species and by employing (stem) cells from relevant cellular origins. The starting point for the study is the remarkable capability of early foetal skin and skin from the spiny mouse (Acomys) to heal perfectly without scars/ contraction and with appendices such as hair follicles. Novel biomaterials and skin substitutes will be developed and evaluated. In order to effectively embrace this new approach, the PhD students need to have knowledge in key elements of basic science, regenerative medicine and biomaterial sciences. As translation to medical devices and especially advanced therapy medicinal products is currently too limited, we will give the PhD students a solid theoretical and practical foundation on topics like regulatory affairs, GMP and GCP, as well as secondments in industry. Driven by both the enthusiasm to gain basic scientific insights and the need for efficacious and innovative therapies, the students will acquire expertise through cutting edge scientific projects and will be trained by leading experts in all required skills to further develop their scientific findings into real life-science products. The SkinTERM program will thus create a new generation of entrepreneurial, multidisciplinary and inter-sectorially trained scientists with excellent career perspectives in either academia, industry or government.

ProgRET will create a multidisciplinary and intersectoral European training network focusing on the mechanisms, diagnosis and therapy of dominantly inherited retinal diseases (IRD). IRD represent a major cause of blindness, affecting 350,000 people in Europe. IRD have long been considered incurable, however major advances have led to groundbreaking new treatments. Today, the most important challenges in the IRD field relate to an unsolved genetic diagnosis, unknown disease mechanisms and gene therapy development for autosomal dominant IRD (adIRD), representing 25–40% of all IRD cases. We have demonstrated an emerging role for splicing factors, structural variants and non-coding defects in patients with adIRD, and developed novel disease models and gene therapies for adIRD. ProgRET aims to dissect adIRD mechanisms using retinal stem cell and aquatic animal models, to advance adIRD diagnostics using a single-molecule multi-omics framework, and to develop innovative treatments based on RNA therapy and CRISPR-genome editing. These challenges will be tackled by integrating unique expertise and cutting-edge technology within ProgRET, including (multi-)omics, bioinformatics, functional genomics, RNA biology, gene regulation, stem cell technology, retinal organoids, animal models, genome editing and gene therapy. ProgRET will give Doctoral Candidates (DCs) unparalleled training opportunities in outstanding academic and industrial settings through training-by-research via individual research projects, secondments, and network-wide training sessions. All individual training and research activities will provide each DC with the necessary skills in academic and industrial research. ProgRET will make a career in both sectors attractive and improve their career prospects. Finally, our multidisciplinary network offers a unique opportunity to accelerate the understanding, diagnostics and therapeutics for adIRD in Europe, and to translate research findings to healthcare and society.