Sepsis is a clinical syndrome caused by a systemic deregulated inflammatory immune response to an infection. Sepsis has a significant 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 leading first to high levels of inflammatory mediators and organ failure, and second to a state of ‘immunoparalysis’ and opportunistic infections. This makes CAP-mediated severe sepsis a life-threatening condition with mortality rates as high as 28-50%.
Adult adipose mesenchymal stem cells (ASCs) are known for their broad capacity to modulate the function of the immune system, and also possess antimicrobial capacities, which make ASCs a potential new treatment candidate for sepsis.
The SEPCELL consortium believes that allogeneic ASCs (obtained from a healthy donor) may be an innovative therapeutic approach 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 for the Intravenous Treatment of Adult Patients with CABP and admitted to the Intensive Care Unit. This trial aims to determine the safety of the ASC treatment, and secondly obtain some indication of potential benefit.
• To identify potential biomarkers that could help to predict the response of the patient to the treatment.
• To understand the mode of action of ASCs in sepsis
Conclusions of the action:
In this project we carried out SEPCELL, the first placebo-controlled trial to assess the safety and efficacy of ASCs in severe CABP. This study demonstrated that ASCs are well tolerated in patients with severe CABP. Overall, the number of reported side effects were similar between the study arms.
Allogeneic MSCs can elicit anti-donor immune responses in recipients, such as the production of antibodies against the cell therapy treatment. Owing to the number of patients in this study, statistical significance between the placebo and the ASC treated arms could not be determined. There is a need for larger studies assessing the potential impact of the immunogenicity on patient outcomes after treatment with eASCs.
Owing to early closure of enrollment, the number of patients recruited into the study was too low to detect differences in clinical outcomes; therefore, it was not possible to draw inferences from this study regarding the effect of eASCs on clinical outcomes. Exploratory biological analyses from blood samples collected during the study, including cell response assessments, RNA expression profiles of leukocytes and protein biomarker levels in leukocytes are ongoing.
This study has several limitations. Firstly, the use of a fixed dose in this study may have limited the observable therapeutic benefit of eASCs. Future studies may consider altering the timing between interventions, administering more than 2 doses, or using a dose-escalation strategy to assess clinical outcomes.
