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.

The incidence of sepsis is increasing due to the aging of the population, an increase of drug-resistant bacteria and weakening of the immune system caused by e.g. HIV infection, cancer treatments or transplant drugs.

While any type of infection (bacterial, viral or fungal) can lead to sepsis, the lung is the leading source of infection both in severe sepsis and in septic shock. Community-acquired pneumonia (CAP) is a common denominator for infections of the lung acquired from normal social contact (i.e. outside of the hospital setting). 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 (infection control and functional support) 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 adult mesenchymal stem cells a potential new treatment candidate for sepsis. Indeed, therapeutic benefit of MSC treatment in in vivo 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 patients
  • To ensure that all regulatory questions on the clinical trial are satisfactory addressed in consultation with national regulatory agencies and ethic´s committees.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the last 18 months, we have been working on trying to better understand the mode of action of ASCs in the context of sepsis. For that several lines of investigation have been develop in order to determine the way ASCs modulate the immune system and bacterial growth. Our results indicate that ASCs may reduce the growth of bacteria in experimental conditions in vitro. We are currently investigating the mechanisms that are involved, that at least in part seem to rely on soluble factors secreted by ASCs.

Sepsis patients are commonly treated with antibiotics and corticosteroids to control the infection and the exacerbated inflammatory response. These treatments may potentially affect the viability of the ASCs and therefore it is important to investigate the effects of these drugs on the ASCs. We carried out in vitro experiments in which we cultured ASCs with clinically relevant concentrations of antibiotics and/or corticosteroids and tested their effect on ASC viability. Our results indicated that ASC viability was not significantly affected.

At later stages of sepsis, and as a consequence of the hyperactivation of the immune system to fight bacteria, there is a high proportion of peripheral blood immune cells dying, which may result in a deficiency of the immune response (immunesuppression) allowing opportunistic infections that may dramatically impact the clinical outcome.

Therefore, any treatment that could reduce the death of immune cells in sepsis may potentially impact positively the evolution of the disease. In this regard, we investigated in vitro the effect of ASCs on death of peripheral blood mononuclear cells and found that ASCs can protect immune cells from death. We are currently investigating the way ASCs do this.

We have been optimizing protocols to identify (in blood samples from patients) potential biomarkers predictive of response at both molecular and cellular level.

We have been optimizing protocols to determine the potential generation of antibodies against the stem cell treatment.

The clinical trial has been initiated already, and patients in Belgium and Spain have been enrolled, randomized and treated. No results are available yet. We are currently working on opening new sites and getting more patients recruited.

Main results obtained so far:

  • Clinical trial initiated in Belgium and Spain.
  • Several patients already treated.
  • Protocols for biomarker identification and immune response against allogeneic ASCs set up.
  • Improved understanding of mode of action of ASCs in the context of sepsis.

Progress beyond the state of the art and expected potential impact

The successful regulatory strategies paved the way to obtain the approvals from national authorities. Thus, the clinical trial is already ongoing.

This trial is an international multicenter, randomized, blinded, placebo controlled trial.

This is the largest trial testing mesenchymal stem cell therapy in sepsis patients, so far. Therefore, the data and information we can collect from this trial may potentially have a remarkable impact at scientific, clinical and patient levels.

The methodologies (at cellular and molecular level) we are setting up to identify potential biomarkers predictive of patient response are of special relevance as they may allow us, once all samples are collected, to determine if there is a “signature” in the patients at baseline that may predict the evolution of the disease after treatment.

Our understanding of the mode of action of ASCs is now deeper.

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