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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

Periodic Reporting for period 3 - 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)

Reporting period: 2018-11-01 to 2020-04-30

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. Community-acquired pneumonia (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.
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’s committees.
During the last 18 months, the Consortium has been highly focused on the recruitment of patients in the clinical trial in Spain, France, Belgium and Lithuania, and their follow up.
In very acute and life-threatening indications, such as sepsis, in which rapid treatment is a need 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 (allogeneic MSCs) and not from the own patient. In that situation, the patient´s immune system would be potentially able to recognize the foreign MSCs used, generating antibodies against them (donor specific antibodies: DSA) that may eventually eliminate them. We have collected plasma samples from SEPCELL patients at baseline and after the treatment and investigated the generation of DSA against the allogeneic adipose stem cells used (Cx611) in some samples. We are currently analyzing the first set of preliminary data we have obtained. Conclusions cannot be taken until all samples are tested and analyzed.
We have additionally collected peripheral blood mononuclear cells (PBMCs) from SEPCELL patients at baseline and after the treatment in order to perform in vitro functional assays (proliferative capacity, phenotype, T cell activation status, early activation markers, cytotoxic activity against Cx611) comparing before and after the treatment as well as comparing with healthy subjects. In this reporting period we have dedicated to mostly optimize the experimental settings with healthy subjects in order to subsequently perform these tests with samples from patients. The experimental settings are defined and initial studies with patients´ samples have been carried out, however these activities have been affected by the COVID-19 pandemic and suffered a delay. Complete analysis and interpretation of the results can only be made once all samples are tested.
We have also collected and stored blood samples from patients to perform the biomarker studies. These studies could not be initiated as a consequence of the COVID-19 pandemic.
In these period two publications reporting the therapeutic effect of Cx611 in non-clinical studies have been published and two other manuscripts are in preparation.
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.
The successful regulatory strategies paved the way to obtain the approvals from national authorities. Thus, we increased our recruitment of 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.
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