Cell and gene therapies holds tremendous therapeutic promise for patients worldwide and represent a valuable global market opportunity. Still, cell-based therapies present challenges related chiefly to cell retention, engraftment and survival. Minimally invasive cell delivery and improved retention by means of an encapsulation technology is a driver for generating more predictable clinical outcomes with lesser immune rejection in a variety of disease areas. Stemmatters has built a highly versatile platform technology to design novel molecules with attributes to safeguard cells and support cell function and retention. Based on a chemically defined template, our technology provides rapid generation of compound libraries supporting establishment of safe, less costly and more effective cell-based therapies. The performance and cost effectiveness of our development platform surpasses competing technologies. NOAHs-ARK (spelled as Noah´s ark) aims to disrupt the current market landscape by developing Stemmatters’ encapsulation platform to other therapeutic applications of large unmet demand. Recruitment and integration of an Innovation associate (IA) with specific expertise in cell-based therapy into Stemmatters is a significant milestone that will dramatically increase Stemmatters capabilities, strengthen existing collaborations, and expand business opportunities. The IA will provide Stemmatters with important technical expertise and a comprehensive understanding of market unmet needs and current competitive dynamics. The IA will lead development of our innovative platform to other therapeutic applications of large unmet need, by designing in vitro studies for specific disease indications in need of enabling cell encapsulation solutions. Biomaterials entering the pipeline will be supported by technical product dossiers to assist regulatory submissions, smooth translation to the clinic and commercialization by strategic licensing and/or supply agreements.

Spinal cord injury (SCI) is a devastating pathology with dramatic lifetime consequences affecting thousands of people worldwide. Therefore, and considering the very limited regeneration ability of the central nervous system, in this project we propose to develop a neural tissue engineered scaffold capable of not only combining fibrous and porous topographic cues in order to mimic the morphology of the native spinal cord, but also potentiating the properties of graphene related materials (GRM) supported in a protein-rich decellularized matrix (adECM). In fact, the suggested 3D microenvironment should present electrical, chemical, mechanical and topographic features able to preserve neural cell survival and enhance neural progenitor cell differentiation towards neuronal and glial cells. Progress in this sense will contribute to a better understanding of the key factors controlling repair in damaged neural tissues and, consequently, bring insights into new therapeutic approaches for spinal cord recovery.

Problem: Cell and gene therapies (CGT) represent a breakthrough in the treatment of a wide range of conditions. However, limited global manufacturing capacity owing to a lack of scalability prevents CGT from becoming widely available to patients: therapies are prepared individually at central facilities in a series of complex open manual steps. Variability is high, and a uniform manufacturing process is lacking. Automated, standardized, quality-controlled, and decentralized processes are urgently needed to scale out CGT manufacturing, bring down costs and enable treatment for millions of patients. True automation requires an understanding of what are known as critical process parameters (CPPs). Currently, manufacturing of cell therapies is carried out over several days, with limited access to knowledge of CPPs, often obtained through intrusive sampling methods. Innovation: We aim to enable in-line continuous monitoring of key cell culture parameters during therapy manufacturing. To do this, we will create a self-contained instrument that connects miniaturized biosensor technologies to a novel bioreactor to allow automation of the entire cell therapy manufacturing process in a closed system. The device will accommodate a disposable, single-use sampling unit that will ultimately be adaptable to any bioreactor. Our platform will carry out continuous, automated, and closed monitoring of a set of well-defined CPPs, as indicators of the overall state of the cell culture. We will select and refine our parameters and establish optimal ranges, as predictors of process outcomes and product quality, based on prediction algorithms and digital twin analysis. This will allow continuous process monitoring, while greatly lowering costs and risks associated with manual sampling. Our first application will be in CAR T cell therapy production, but the advantages of automation with continuous monitoring will be further applied to other CGT product that involves culturing of cells.

Although immunotherapy of select hematological malignancies using Chimeric Antigen Receptor (CAR) redirected T lymphocytes has recently gained regulatory approval, successful treatment of solid tumors using CAR T cells remains elusive. One salient problem is the limited efficacy and untimely exhaustion of CAR T cells in the tumor microenvironment (TME). Combining innovative methods of genome editing, chemistry and immunology, CAR T-REX proposes to explore a novel concept of building auto-regulated genetic circuits into CAR T cells to selectively circumvent their exhaustion upon activation in the TME. Genetic rewiring will be achieved by precisely inserting artificial miRNAs under endogenous exhaustion-related “Driver” promoters to downregulate “Target” genes that cause exhaustion. Proprietary technology enables specific replacement of the “Driver” gene without risking off-target mutations. Further advantages of combined insertion and silencing are (i) the ability to regulate when a gene is turned on/off by biologically and clinically relevant cellular cues, and (ii) multiple gene-knockdown with a single dsDNA cleavage and RNA-silencing of both alleles. These genetic modifications will be implemented using a novel high-performance peptide-based gene delivery platform with unlimited loading capacity, allowing combination of several types of cargo, as well as economical large scale GMP production. Rewired HER2/Neu (ErbB2) redirected CAR T cells will be tested on preclinical breast and gastric carcinomas, and variants that eliminate tumors resistant to conventional 2nd and 3rd generation peers (without adverse events) will be developed/manufactured following quality-by-design principles under GMP-like conditions, thus accelerating the pathway towards clinical translation. These approaches will also constitute a proof-of-concept for modifying therapeutic cell products, with the potential to considerably improve their safety, specificity, efficacy, scalability and cost.