PMID- 34659208 OWN - NLM STAT- MEDLINE DCOM- 20211222 LR - 20211222 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Apoptotic Cells for Therapeutic Use in Cytokine Storm Associated With Sepsis- A Phase Ib Clinical Trial. PG - 718191 LID - 10.3389/fimmu.2021.718191 [doi] LID - 718191 AB - BACKGROUND: Sepsis has no proven specific pharmacologic treatment and reported mortality ranges from 30%-45%. The primary aim of this phase IB study was to determine the safety profile of Allocetra-OTS (early apoptotic cell) infusion in subjects presenting to the emergency room with sepsis. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action. METHODS: Ten patients presenting to the emergency room at the Hadassah Medical Center with sepsis were enrolled in this phase Ib clinical study. Enrolled patients were males and females aged 51-83 years, who had a Sequential Organ Failure Assessment (SOFA) score >/=2 above baseline and were septic due to presumed infection. Allocetra-OTS was administered as a single dose (day +1) or in two doses of 140x10(6) cells/kg on (day +1 and +3), following initiation of standard-of-care (SOC) treatment for septic patients. Safety was evaluated by serious adverse events (SAEs) and adverse events (AEs). Organ dysfunction, ICU and hospital stays, and mortality, were compared to historical controls. Immune modulator agents were measured using Luminex((R)) multiplex analysis. RESULTS: All 10 patients had mild-to-moderate sepsis with SOFA scores ranging from 2-6 upon entering the study. No SAEs and no related AEs were reported. All 10 study subjects survived, while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU stays compared to matched historical controls (p<0.0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines, and additional immune modulators that gradually decreased following treatment. CONCLUSION: Administration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03925857. (https://clinicaltrials.gov/ct2/show/study/NCT03925857). CI - Copyright (c) 2021 van Heerden, Abutbul, Sviri, Zlotnick, Nama, Zimro, el-Amore, Shabat, Reicher, Falah and Mevorach. FAU - van Heerden, Peter Vernon AU - van Heerden PV AD - General Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Abutbul, Avraham AU - Abutbul A AD - Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Sviri, Sigal AU - Sviri S AD - Medical Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Zlotnick, Eitan AU - Zlotnick E AD - Rheumatology and Rare Disease Research Center, The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center and School, Jerusalem, Israel. FAU - Nama, Ahmad AU - Nama A AD - Department of Emergency Medicine, Hadassah-Hebrew University Medical Center and School, Jerusalem, Israel. FAU - Zimro, Sebastian AU - Zimro S AD - General Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - El-Amore, Raja AU - El-Amore R AD - Rheumatology and Rare Disease Research Center, The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center and School, Jerusalem, Israel. FAU - Shabat, Yehudit AU - Shabat Y AD - Department of Research, Enlivex Therapeutics Ltd., Ness-Ziona, Israel. FAU - Reicher, Barak AU - Reicher B AD - Department of Research, Enlivex Therapeutics Ltd., Ness-Ziona, Israel. FAU - Falah, Batla AU - Falah B AD - Department of Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Mevorach, Dror AU - Mevorach D AD - Rheumatology and Rare Disease Research Center, The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center and School, Jerusalem, Israel. AD - Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. LA - eng SI - ClinicalTrials.gov/NCT03925857 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210930 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Autoantibodies) RN - 0 (Biomarkers) RN - 0 (Immunologic Factors) SB - IM MH - Aged MH - Aged, 80 and over MH - *Apoptosis MH - Autoantibodies MH - Autoimmunity MH - Biomarkers MH - Cell- and Tissue-Based Therapy/adverse effects/*methods MH - Cytokine Release Syndrome/blood/*complications/diagnosis/*therapy MH - Disease Management MH - Disease Susceptibility MH - Female MH - Humans MH - Immunologic Factors MH - Male MH - Middle Aged MH - Organ Dysfunction Scores MH - Sepsis/blood/*complications/diagnosis/*therapy MH - Treatment Outcome PMC - PMC8515139 OTO - NOTNLM OT - Inflammation OT - apoptotic cells OT - cell therapeutics OT - cytokine storm OT - pneumonia OT - sepsis COIS- PvH received honoraria from Enlivex Ltd as a consultant. DM is the founder, and CMO of Enlivex Therapeutics Ltd. YS and BR are part of the research team of Enlivex Therapeutics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. EDAT- 2021/10/19 06:00 MHDA- 2021/12/24 06:00 PMCR- 2021/09/30 CRDT- 2021/10/18 08:55 PHST- 2021/05/31 00:00 [received] PHST- 2021/09/14 00:00 [accepted] PHST- 2021/10/18 08:55 [entrez] PHST- 2021/10/19 06:00 [pubmed] PHST- 2021/12/24 06:00 [medline] PHST- 2021/09/30 00:00 [pmc-release] AID - 10.3389/fimmu.2021.718191 [doi] PST - epublish SO - Front Immunol. 2021 Sep 30;12:718191. doi: 10.3389/fimmu.2021.718191. eCollection 2021.