Periodic Reporting for period 5 - 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: 2021-11-01 to 2022-04-30
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.
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.
We have mostly focused on solving some methodological issues identified after initial analysis of patient biomarkers that could bias the conclusions, and fine tuning the analysis and interpretation of the data. Unfortunately, we could not fully complete any analysis and further dedication beyond the duration of the project will be needed to confirm whether the preliminary findings observed are confirmed and significant.
Our data indicate that eASCs induced a limited immune response in a sCABP patients. These results should be interpreted cautiously due to a relatively small sample size. Further work is needed to confirm these observations.
In the initial analyses of the host response comparing patients treated with eASC and the placebo group, we found a limited number of significanlty altered genes attributable to the treatment. Additionally, our data indicate modulation of gene pathways related to the immune system, hemostasis and repair mechanisms after the treatment with eASCs.
We have measured a set of plasma biomarkers indicative of the host response in sepsis and pneumonia and of pathophysiological processes that may be influenced by eASC treatment. We identified several potential candidates, but further work to confirm these observations are needed.
We focused on preparing a manuscript to report the clinical trial results and minor follow up activities after the end of the trial, like posting the clinical trial results in the registry.
Importantly, the primary endpoint of the trial has been achieved as safety of the cell therapy arm has been comparable to patients treated with placebo. The results obtained in this trial indicate that intravenous administration of eASCs in critically ill patients is safe. Although further studies are needed, these results further support the investigation of stem cell-based therapies for this type of patients.
The experience gained in this complex trial may be of interest to others facing or planning trials in similar indications or with similar therapeutic treatments.
Main results obtained so far:
• Clinical trial finished and primary safety endpoint achieved
• Limited immune response against intravenously administered allogeneic ASCs in patients
• Potential biomarker candidates identified. Further work needed to confirm these results
• Improved understanding of mode of action of ASCs in the context of sepsis
• Clinical trial manuscript finalized and under evaluation
Our data indicate that eASCs induced a limited immune response in a sCABP patients. These results should be interpreted cautiously due to a relatively small sample size. Further work is needed to confirm these observations.
In the initial analyses of the host response comparing patients treated with eASC and the placebo group, we found a limited number of significanlty altered genes attributable to the treatment. Additionally, our data indicate modulation of gene pathways related to the immune system, hemostasis and repair mechanisms after the treatment with eASCs.
We have measured a set of plasma biomarkers indicative of the host response in sepsis and pneumonia and of pathophysiological processes that may be influenced by eASC treatment. We identified several potential candidates, but further work to confirm these observations are needed.
We focused on preparing a manuscript to report the clinical trial results and minor follow up activities after the end of the trial, like posting the clinical trial results in the registry.
Importantly, the primary endpoint of the trial has been achieved as safety of the cell therapy arm has been comparable to patients treated with placebo. The results obtained in this trial indicate that intravenous administration of eASCs in critically ill patients is safe. Although further studies are needed, these results further support the investigation of stem cell-based therapies for this type of patients.
The experience gained in this complex trial may be of interest to others facing or planning trials in similar indications or with similar therapeutic treatments.
Main results obtained so far:
• Clinical trial finished and primary safety endpoint achieved
• Limited immune response against intravenously administered allogeneic ASCs in patients
• Potential biomarker candidates identified. Further work needed to confirm these results
• Improved understanding of mode of action of ASCs in the context of sepsis
• Clinical trial manuscript finalized and under evaluation
This trial is an international multicenter, randomized, blinded, placebo controlled trial. To our knowledge this is the largest trial testing MSC therapy in critically ill patients, so far. Therefore, the experience, data and information collected from this trial may be interest at scientific, clinical and patient levels.
The methodologies 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 problems we encountered (like batch to batch variability) and the solutions we provided may be also informative for the general scientific community.
The demonstration that MSCs can safely be administered intravenously in critically ill patients is also of importance as may help others to further develop their stem cell-based therapeutic candidates in the clinic.
The methodologies 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 problems we encountered (like batch to batch variability) and the solutions we provided may be also informative for the general scientific community.
The demonstration that MSCs can safely be administered intravenously in critically ill patients is also of importance as may help others to further develop their stem cell-based therapeutic candidates in the clinic.