Mesenchymal stromal cells as an advanced therapy medicinal product to reverse sepsIs-induced immunoparalysis – ESSENTIEL

Sepsis is defined as life-threatening organ dysfunction caused by a deregulated immune host response to infection. This syndrome involves a pro-inflammatory, anti-inflammatory state as well as an immunoparalysis at the origin of an increased susceptibility to secondary infections. Sepsis is estimated to affect, every year, around 3,4 million Europeans and cause almost 700 000 deaths.
With respect to the mortality of sepsis and the impact of nosocomial pneumonia and multi-resistant bacteria in critically ill patients, identifying innovative therapeutic strategies in sepsis is considered as a public health priority.
Currently, there is no specific treatment for sepsis due to its complex pathophysiology, which combines inflammation and immunoparalysis. Although several clinical trials targeting the pro-inflammatory phase are underway, few drug candidates are being studied for the treatment of the associated immunoparalysis, which is a source of secondary infections and poor prognosis.

Thanks to their immunomodulatory properties, their capacity to migrate to damaged tissues contributing to their repair, and their antimicrobial effect, mesenchymal stromal cells (MSC) appear as very attractive candidates for the treatment of sepsis, septic shock and COVID19. In specific environment, they are able to adopt an immunostimulating or an immunomodulating phenotype mediated by the activation of their toll like receptors (TLR). In a cell anergy context, as that seen in sepsis-associated immunoparalysis, they could exhibit a pro-inflammatory phenotype (MSC1), making it possible to reduce apoptosis and promote T-cell survival. So, we hypothesize that it could be of great interest to take advantage of their immunoprotective effects, considering that MSC could then reverse immunoparalysis state, thus preventing the development of secondary infections such as pneumonia, reducing sepsis mortality.

In this context, umbilical cord matrix and more precisely Wharton’s Jelly (WJ) could be an advantageous tissue source of MSC. Thus, we propose an innovative model of cell therapy based on personalized medicine using primed WJ-MSC produced as an Advanced Therapy Medicinal Product (ATMP) in sepsis or septic shock.
The challenges of this project are: (i) producing WJ-MSC in a stirred bioreactor using microcarriers allowing cell expansion, followed by priming into the MSC1 phenotype and comparison with 2D expansion as gold standard control, (ii) investigating in vitro, the MSC1 polarization mechanism, its immune properties and its stability, (iii) evaluating ex vivo MSC1 effect on immune cells from patients with severe pneumonia-related sepsis, known to be associated with secondary ICU-acquired infections and identifying relevant biomarkers likely to predict immunoparalysis reversion by MSC1 and (iv) evaluating in vivo MSC1 effect on immunoparalysis in a model of secondary bacterial pneumonia in post-septic mice.
The project is based on the complementary skills of research teams (IMoPA, CEA, Institut Cochin), specialists in WJ-MSC production in clinical grade (UTCT and start-up StemInov) and clinicians belonging to 3 intensive medicine departments and allowing the multicentric recruitment of patients.
Beyond scientific benefits, the ESSENTIEL project will bring benefits for society, as currently, the sepsis-immunoparalysis remains an unmet medical need. To this regard, the ESSENTIEL project is a collaborative translational research project allowing the first ATMP in this indication. It will lead, in medium-term, to propose a Clinical Research Program (PHRC) supported by the DGOS Hospital to validate this new therapeutic approach.