Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - SEPCELL (Title of Proposal: Restoring the immune system homeostasis and organ function in severe community acquired pneumonia- induced sepsis through adipose derived allogeneic stem cells (SEPCELL Proje)

Teaser

When pathogens enter our body, our immune cells can sense these microorganisms which results in the initiation of an immune response aimed at eliminating the invading pathogen. When bacteria overcome the ability of the immune system to clear the infection, the interactions...

Summary

When pathogens enter our body, our immune cells can sense these microorganisms which results in the initiation of an immune response aimed at eliminating the invading pathogen. When bacteria overcome the ability of the immune system to clear the infection, the interactions between pathogens and immune cells may advance into an uncontrolled inflammatory response that no longer benefits the host.
Sepsis is a clinical syndrome caused by a systemic deregulated inflammatory immune response to an infection. The term ‘severe sepsis’ describes instances in which sepsis is complicated by acute organ dysfunction. Severe sepsis has a significant and increasing impact on public health, and is one of the leading causes of mortality in the intensive care units in the developed world.
While any type of infection can lead to sepsis, the lung is the leading source of infection in severe sepsis. Community-acquired pneumonia (CAP) is a common denominator for infections of the lung acquired from normal social contact. CAP is a leading cause of death if complicated by the development of sepsis.
The pathophysiologic mechanism of CAP-mediated severe sepsis is the complete dysregulation of the patient´s immune system. In an initial phase, the systemic hyperactivation of the host immune response against infection leads to high levels of inflammatory mediators, systemic vasodilatation, micro-vascular thrombosis and organ failure. In a second phase, the exaggerated activation of the immune response leads to a state of ‘immunoparalysis’, which is characterized by the occurrence of secondary, opportunistic infections. This makes CAP-mediated severe sepsis a life-threatening condition with mortality rates as high as 28-50%.
The current standard of care does not improve the high mortality and, thus, CAP-mediated severe sepsis represents a major unmet medical need with a huge social burden. Therefore, treatments with the potential to modulate both the initial exacerbated immunoactivation and the subsequent immunosuppression are needed.
Adult mesenchymal stem cells(MSCs), including adipose mesenchymal stem cells(ASCs), are known for their broad capacity to modulate the function of the immune system, targeting multiple pro- and anti-inflammatory pathways. Importantly, MSCs also possess antimicrobial capacities (releasing compounds that kill bacteria and promoting the capacity of immune cells to eat bacteria). Both properties(immunomodulatory and antimicrobial) make cell therapy with MSCs a potential new treatment candidate for sepsis. Indeed, therapeutic benefit of MSCs in experimental models of sepsis has been extensively reported.
The SEPCELL consortium believes that cell therapy with allogeneic ASCs (obtained from a healthy donor, to treat a patient) may be an innovative therapeutic approach in order to re-establish the normal immune response of severe sepsis patients, reducing organ injury and restoring organ functionality. A phase Ia/IIb clinical trial will be performed to test this possibility.
Project objectives:
•To carry out a multicenter, placebo controlled clinical trial (entitled “Phase Ib/IIa, Randomised, Double Blind, Parallel Group, Placebo Controlled, Multicentre Study to Assess the Safety and Efficacy of Expanded Cx611 Allogeneic Adipose-derived Stem Cells (eASCs) for the Intravenous Treatment of Adult Patients With Severe Community-acquired Bacterial Pneumonia and Admitted to the Intensive Care Unit”. This trial aims to firstly determine the safety of the ASC treatment in this patient population, and secondly obtain some indication of potential benefit of the treatment.
•To identify potential “signals” in blood samples of patients (biomarkers) that could help to predict the response of the patient to the treatment.
•To understand the mode of action of ASCs in sepsis
•To ensure that all regulatory questions on the clinical trial are satisfactory addressed in consultation with national regulatory agencies and ethic

Work performed

During the last 18 months, the Consortium has been working on further understanding the anti-microbial properties of ASCs and the mechanisms by which they modulate the immune function against bacteria. We found that ASCs can inhibit bacterial growth in vitro through mechanisms that rely, at least in part, in soluble factors they release. We identified some of the factors that may be potentially involved, and we are currently further investigating their direct role.
One of the mechanisms that have been implicated in the potential therapeutic properties of mesenchymal stem cells to treat sepsis, is their capacity to modulate the function of monocytes, macrophages and dendritic cells, immune cells reported to play important roles in sepsis. We carried out in vitro studies in which we investigated the capacity of ASCs to modulate the function of these immune cells. We found that the presence of ASCs made monocytes, macrophages and dendritic cells less inflammatory and more anti-inflammatory, more phagocytic of bacteria and with reparative properties, supporting the notion that ASCs modulate the function of the immune system in a way that would be beneficial in the context of sepsis.
In very acute and life-threatening indications, such as sepsis, in which rapid treatment is a needed and patients have to be treated within few hours, mesenchymal stem cells cannot be obtained from the patient, but have to be ready and available at the hospital. Therefore, the preferred option is that MSCs are obtained from healthy donors and not from the own patient (allogeneic MSCs). In that situation, the patient´s immune system would be potentially able to recognize the foreign MSCs used, generating antibodies against them that may eventually eliminate them. We have investigated the capacity of the immune system to recognize and eliminate allogeneic ASCs in vitro. Differences between donors were investigated and we identified molecules expressed in the surface of ASCs that seem to play a key role in the process, which open theoretically the option to modulate this patient´s immune system/allogeneic ASC interaction and recognition. Further investigation with blood samples from patients will be carried out.
Finally, protocols for biomarker studies with blood samples from patients comparing before and after the treatment have been optimized.
Main results obtained so far:
•Clinical trial ongoing in several European countries.
•Protocols for biomarker identification and immune response against allogeneic ASCs optimized.
•Improved understanding of mode of action of ASCs in the context of sepsis.

Final results

The successful regulatory strategies paved the way to obtain the approvals from national authorities. Thus, we are recruiting patients in several European countries.
This trial is an international multicenter, randomized, blinded, placebo controlled trial. This is the largest trial testing MSC therapy in sepsis patients, so far. Therefore, the data and information that can be collected from this trial may potentially have a remarkable impact at scientific, clinical and patient levels.
The methodologies (at cellular and molecular level) that are being set up to identify potential biomarkers predictive of patient response are of special relevance as they may allow to determine if there is a “signature” in the patients at baseline that may predict the evolution of the disease after treatment.
The understanding of the mode of action of ASCs is now deeper.

Website & more info

More info: http://www.sepcell.eu/.