The research and training objectives of the INsTRuCT Consortium reflect its central purpose of accelerating development of MRC-based therapies. INsTRuCT’s research program has been divided in to four scientific work-packages (WP) structured according to the major phases of drug development, namely - (WP1) Basic Science, (WP2) Manufacturing Technology, (WP3) Preclinical Development, and (WP4) Clinical Testing.
Cell therapy is a fast-paced discipline in which basic scientific concepts are rapidly assimilated into new therapeutic approaches. WP1 is concerned with basic scientific investigation of MRC that will lead to innovative approaches to generating cell products with greater stablility and potency. The four projects in WP1 concern fundamental questions about MRC differentiation and stability, but Early Stage Reseachers (ESR) will also be encouraged to think about potential technological applications of their basic discoveries. ESR1 and ESR2 will investigate metabolic regulation of monocyte differentiation into macrophages and DC. ESR3 and ESR4 will focus on epigenetic mechanisms controlling monocyte differentiation and commitment to stable suppressor function. ESR7 will undertake a bioinformatics project studying transcriptional regulation of monocyte differentiation. Innovations stemming from WP1 will include new methods for enhancing MRC phenotype and function through manipulation of cellular metabolism, epigenetic control of gene expression, drug treatments or genomic editing.
WP1 is led by Dr. Silvia Gregori of Ospedale San Raffaele, Milan, Italy.
WP2 is a technological package concentrating on development of novel GMP techniques and devices that will lead to more reliable and affordable manufacturing procedures for MRC-based therapeutic products. Future development of automated cell processing devices will reduce production costs and lead to greater procedural standardisation. Likewise, innovative approaches to cell culture, including manufacture of composite cell products or producing cells within implantable scaffolds, could greatly enhance clinical effectiveness in routine applications. New approaches for labelling therapeutic cell preparations will allow their distribution and survival to be monitored in patients using imaging techniques or biochemical assays. ESR5 will take a Data Science approach to understanding manufacture of MRC-based cell products and how specific production methods impact those products’ biological and pharmaceutical qualities. ESR8 will be trained by an industrial beneficiary that is developing an automated, fully closed manufacturing process for myeloid cell products transfected with antigen-encoding mRNA; in particular, ESR8 will implement innovative pharmaceutical assays for MRC identity and potency using in-line analytical systems. ESR11 aims to establish an affordable, scalable, robust and reproducible production process for tolerogenic DC (tolDC) products using cutting-edge automated systems for sterile manufacturing. Innovations stemming from WP2 will include new processes and technologies for safer, cheaper and more reliable production of next-generation MRC-based cell products that will be exploited in WP3 (Preclinical Development) and WP4 (Clinical Testing).
WP2 is led by Prof. Nathalie Cools of University of Antwerp, Belgium
WP3 considers MRC-based cell therapy from a pharmacological perspective. Although CBMPs are quite different in nature from chemically synthesized drugs or biologics, many of the same general considerations apply to their clinical use. In order to use any therapeutic agent safely and effectively, clinicians must know about its pharmacological properties and how these predict safety and response in individual patients. Specifically, clinicians must know about the pharmacokinetics (ie. absorption, tissue distribution, metabolism, and elimination) and therapeutic dose-range of a drug, as well as having an understanding of its mechanism of action and potential adverse effects. WP3 recognises the importance of formality and robustness in preclinical studies, as well as commercialization of innovative technologies emerging from individual projects. This work-package is specifically concerned with the pharmacological characterization of MRC-based cell products. ESR6 will explore the relationship between cellular metabolism and the properties of autologous tolerogenic dendritic cells (ATDC) in order to develop a more potent cell product. ESR10 will study the effects of MRC infusion on recipient T cell and B cell responses using a battery of functional immune monitoring assays. ESR12 will develop innovative bioinformatic methods for image analysis that will then be applied to the detection of MRC in human tissue specimens. ESR14 will take a functional screening approach to identifying novel mechanisms by which Mregs drive conversion of naïve T cells into iTregs. Innovations stemming from WP3 will include new MRC-based cell products, new co-treatments to potentiate the pharmacodynamic actions of MRC-based therapies, and new clinical assays to evaluate the immunological effects of MRC therapy in patients.
WP3 is led by Dr. Aurélie Moreau of the Centre of Research in Transplantation and Immunology, University of Nantes, France.
WP4 is a translational work-package that addresses important questions about the behaviour and clinical effects of MRC-based therapy in patients. WP4 is dedicated to understanding the impact of patient pathophysiology, immunogenetics and concomitant drug therapy on the safety and effectiveness of MRC-based therapies, which will lead to future optimization of clinical procedures, such as cell collection by leucapheresis, cell administration and clinical assessment of patients. ESR9 will undertake a bioinformatics project in personalized medicine, in which datasets obtained from The ONE Study trials and other sources will be analysed to identify biomarkers associated with favourable responses to cell-based therapies or that stratify patients according to risk of clinical complications. ESR13 will participate in the immune monitoring and analysis of an on-going multicenter clinical trial of “tolDC-VitD3” therapy in patients with active MS. ESR15 will be involved in developing and validating a GMP-compliant method for 19F-labelling of tolDC in order to track these cells in patients after administration to patients with RA via different anatomical routes. Innovations stemming from WP4 will include new clinical strategies for applying and tracing MRC after administration to patients, as well as new approaches to patient selection and interpretation of clinical outcomes.
WP4 is led by Prof. Eva Martinez Cáceres of the Institute of the Germans Trias i Pujol Foundation, Barcelona, Spain.