Periodic Reporting for period 2 - ImmunoSep (Personalized immunotherapy in sepsis: a precision medicine based approach)
Berichtszeitraum: 2021-07-01 bis 2022-12-31
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to a bacterial, fungal or viral infection. Despite the progress of medical field in the last two decades, it is still characterized by a high mortality reaching 30-40%. In the developed world sepsis is the most frequent common cause of death in non-coronary Intensive Care Units (ICUs).
Treatment of sepsis has been characterized by two revolutionary steps that significantly decreased mortality: the introduction of antibiotics, and the development of ICUs. It has been widely hoped that a third revolution, immunotherapy, would further improve the outcome of the disease. However, thus far immunotherapy has been unsuccessful due to the fact that the pathophysiological mechanisms of sepsis are still incompletely understood, and the heterogeneity of the disease is a major clinical challenge. The early model of an overwhelming inflammatory reaction failed to capture the complex pathophysiology of the syndrome, and the studies aiming to reverse immune paralysis in sepsis through a ‘one size fits all’ strategy.
In order to address this gap in our knowledge to treat sepsis, ImmunoSep proposes that while overinflammation and immunoparalysis critically contribute to sepsis pathophysiology, they are present in individual sepsis patients to a different extent and in a time-dependent manner. Only a precision medicine-based approach for immunotherapy will be able to significantly improve the outcome of this severe clinical condition. The immune status needs to be determined in each sepsis patient and, based on that, host-directed immunotherapy should be initiated in a personalized manner.
The mission of the project is to design and perform a proof-of-concept clinical trial of personalized immunotherapy in sepsis. Within this clinical trial, a next-generation theranostics platform for the design of future personalized immunotherapy trials in sepsis will be developed. This theranostics platform will be based on an integrated, multi-dimensional systems biology analysis of omics-based datasets, to identify biomarkers, clinical endotypes, and therapeutic targets needed for precision medicine approaches. The final aim of the project is to identify a new paradigm in the treatment of sepsis and to improve the outcome of the population of sepsis patients
Treatment of sepsis has been characterized by two revolutionary steps that significantly decreased mortality: the introduction of antibiotics, and the development of ICUs. It has been widely hoped that a third revolution, immunotherapy, would further improve the outcome of the disease. However, thus far immunotherapy has been unsuccessful due to the fact that the pathophysiological mechanisms of sepsis are still incompletely understood, and the heterogeneity of the disease is a major clinical challenge. The early model of an overwhelming inflammatory reaction failed to capture the complex pathophysiology of the syndrome, and the studies aiming to reverse immune paralysis in sepsis through a ‘one size fits all’ strategy.
In order to address this gap in our knowledge to treat sepsis, ImmunoSep proposes that while overinflammation and immunoparalysis critically contribute to sepsis pathophysiology, they are present in individual sepsis patients to a different extent and in a time-dependent manner. Only a precision medicine-based approach for immunotherapy will be able to significantly improve the outcome of this severe clinical condition. The immune status needs to be determined in each sepsis patient and, based on that, host-directed immunotherapy should be initiated in a personalized manner.
The mission of the project is to design and perform a proof-of-concept clinical trial of personalized immunotherapy in sepsis. Within this clinical trial, a next-generation theranostics platform for the design of future personalized immunotherapy trials in sepsis will be developed. This theranostics platform will be based on an integrated, multi-dimensional systems biology analysis of omics-based datasets, to identify biomarkers, clinical endotypes, and therapeutic targets needed for precision medicine approaches. The final aim of the project is to identify a new paradigm in the treatment of sepsis and to improve the outcome of the population of sepsis patients
The main focus of the project is to perform a clinical trial of immunotherapy in sepsis. 29 clinical sites for the study have been established in 5 countries. Despite the difficulties provided by the COVID-19 pandemic, the ImmunoSep partners have managed to progress with the organization of the clinical trial as planned, with minimal delays. These delays were due to the fact that all the participant sites were departments of infectious diseases and/or intensive care, that were heavily involved in COVID-19. However, despite this initial delay which occurred especially in the period of march-june 2020, all clinical sites managed to recover thereafter and performed the tasks assigned within ImmunoSep.
Within the workplan assigned at the beginning of the project, the clinical protocol of the trial has been written and approved in all countries. The protocol and ICF versions in English and various local languages of the participating countries have been completed. Registration of the ImmunoSep study to receive one EudraCT number has been completed, and the trial is registered with number 2020-005768-74. The study was submitted to and approved by the National Ethics Committee of Greece (approval 2/21; dated 22 Jan 2021 month 11) and by the National Organization for Medicines of Greece (approval IS008/21; dated 18 Feb 2021 month 12). Study registration at Clinicaltrials.gov has been completed, with the registration number NCT04990232. The ethical approvals for the other local clinical sites have been also completed in the second part of 2021 and the first half of 2022. The study is ongoing in the 29 clinical sites in Greece, Netherlands, Germany, Romania and Switzerland. During the period covered by the report, the consortium already recruited approximately half of the planned patients. Considering the speed of recruitment during the last months, it is expected that the trial will be finished during the next 12 months, as planned in the workplan of the project.
In addition to the organization of the clinical trial, the study also aims to identify new biomarkers for the immunological phenotyping of sepsis patients on the one hand, as well as a theranostics platform based on an integrated, multi-dimensional systems biology analysis of omics-based datasets, to identify clinical endotypes and therapeutic targets needed for precision medicine approaches in sepsis. Standard Operating Procedures for sample collection and processing have been established, and protocols have been optimized and tested. Sample collection has started in parallel with the recruitment of the patients. ImmunoSep partners have optimized data handling and analysis pipelines to ensure timely data processing and investigation for transcriptomics and epigenomics. Data analysis of the omics datasets will be initiated after month 30 when these data will become available.
Within the workplan assigned at the beginning of the project, the clinical protocol of the trial has been written and approved in all countries. The protocol and ICF versions in English and various local languages of the participating countries have been completed. Registration of the ImmunoSep study to receive one EudraCT number has been completed, and the trial is registered with number 2020-005768-74. The study was submitted to and approved by the National Ethics Committee of Greece (approval 2/21; dated 22 Jan 2021 month 11) and by the National Organization for Medicines of Greece (approval IS008/21; dated 18 Feb 2021 month 12). Study registration at Clinicaltrials.gov has been completed, with the registration number NCT04990232. The ethical approvals for the other local clinical sites have been also completed in the second part of 2021 and the first half of 2022. The study is ongoing in the 29 clinical sites in Greece, Netherlands, Germany, Romania and Switzerland. During the period covered by the report, the consortium already recruited approximately half of the planned patients. Considering the speed of recruitment during the last months, it is expected that the trial will be finished during the next 12 months, as planned in the workplan of the project.
In addition to the organization of the clinical trial, the study also aims to identify new biomarkers for the immunological phenotyping of sepsis patients on the one hand, as well as a theranostics platform based on an integrated, multi-dimensional systems biology analysis of omics-based datasets, to identify clinical endotypes and therapeutic targets needed for precision medicine approaches in sepsis. Standard Operating Procedures for sample collection and processing have been established, and protocols have been optimized and tested. Sample collection has started in parallel with the recruitment of the patients. ImmunoSep partners have optimized data handling and analysis pipelines to ensure timely data processing and investigation for transcriptomics and epigenomics. Data analysis of the omics datasets will be initiated after month 30 when these data will become available.
The approaches envisaged and proposed by ImmunoSep for the patient stratification and biomarker-based immunotherapy are valid not only for sepsis, but also for other infectious and non-infectious diseases. This approach has been proven exceptionally valuable also in the context of the COVID-19 pandemic. Blood transcriptomes served as a surrogate of the COVID-19-driven immune host response and profiled for a data-driven patient stratification based on molecular phenotype. This analysis allowed prediction of patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host (published by ImmunoSep partners in Genome Med. 2021; 13:7). Similarly, single-cell transcriptomics was used to delineate alterations in the circulating peripheral immune cells in correlation to disease severity. Severe COVID-19 was characterized by a dysregulated myeloid cell compartment, which would enable more specific therapeutic target in patients with this severe disease (published in Cell. 2020 Aug 5:S0092-8674(20)30992-2). In addition, similar approaches have been employed by ImmunoSep partners in community-acquired pneumonia.
These findings demonstrate the validity of the concepts that sit at the basis of ImmunoSep, and that the discoveries that will follow based on the clinical trial organized will likely revolutionize not only the treatment of sepsis, but also of other infections (and possible other immune-mediated diseases).
These findings demonstrate the validity of the concepts that sit at the basis of ImmunoSep, and that the discoveries that will follow based on the clinical trial organized will likely revolutionize not only the treatment of sepsis, but also of other infections (and possible other immune-mediated diseases).