PMID- 37600829 OWN - NLM STAT- MEDLINE DCOM- 20230822 LR - 20230914 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - Apoptotic cells for treatment of acute respiratory distress syndrome associated with COVID-19. PG - 1242551 LID - 10.3389/fimmu.2023.1242551 [doi] LID - 1242551 AB - BACKGROUND: Hyper-inflammatory immune response, a hallmark of severe COVID-19, is associated with increased mortality. Acute respiratory distress syndrome (ARDS) is a common manifestation. We undertook two phase I/II studies in five and then 16 subjects with severe/critical COVID-19 to assess the safety and preliminary efficacy of apoptotic cells (Allocetra-OTS, Enlivex Therapeutics), a cellular immunomodulatory therapy that reprograms macrophages to reduce hyper-inflammatory response severity. METHODS: Eligible patients presenting to the Emergency Room with severe COVID-19 and respiratory dysfunction received one intravenous administration of Allocetra-OTS and were monitored for adverse events (AEs) for 28 days. The primary aim was to determine the safety profile of treatment; secondary aims were recovery from ARDS, intensive care unit (ICU) and hospital length-of-stay, and mortality. Immune modulator markers were measured to elucidate the mechanism of action of Allocetra-OTS. RESULTS: 21 patients with severe-critical COVID-19 of Gamma, Alpha and Delta variants, were treated with a single dose of apoptotic cells. 19/21 patients had mild-to-severe ARDS at presentation. Median age was 53 years, 16/21 were males, 16/21 were overweight/obese. No serious related adverse events (SAEs) were reported. All 21 study subjects survived to day 28 (end of study); 19/21 recovered completely. Comparable mortality rates at the hospital were 3.8%-8.9% for age- and gender-matched patients, and 39%-55% for critical patients. Recovering patients exhibited rapid ARDS resolution and parallel resolution of inflammation markers and elevated cytokines/chemokines. CONCLUSION: In patients with severe/critical COVID-19 associated with ARDS, Allocetra-OTS was safe, well-tolerated, and showed promising results for resolution of respiratory failure and inflammation. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/study/NCT04513470, https://clinicaltrials.gov/ct2/show/study/NCT04590053, Identifiers NCT04513470, NCT04590053. CI - Copyright (c) 2023 van Heerden, Abutbul, Naama, Maayan, Makram, Nachshon, abu Jabal, Hershkovitz, Binder, Shabat, Reicher 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 - Naama, Ahmad AU - Naama A AD - Department of Emergency Medicine, Hadassah-Hebrew University Medical Center and Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel. FAU - Maayan, Shlomo AU - Maayan S AD - Infectious Diseases Division, Barzilai Medical Center, Ashkelon, Israel. FAU - Makram, Nassar AU - Makram N AD - Infectious Diseases Division, Barzilai Medical Center, Ashkelon, Israel. FAU - Nachshon, Akiva AU - Nachshon A AD - General Intensive Care Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Abu Jabal, Kamal AU - Abu Jabal K AD - Ziv Medical Center and Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel. FAU - Hershkovitz, Oren AU - Hershkovitz O AD - Enlivex Therapeutics Ltd., Ness Ziona, Israel. FAU - Binder, Lior AU - Binder L AD - Enlivex Therapeutics Ltd., Ness Ziona, Israel. FAU - Shabat, Yehudit AU - Shabat Y AD - Enlivex Therapeutics Ltd., Ness Ziona, Israel. FAU - Reicher, Barak AU - Reicher B AD - Enlivex Therapeutics Ltd., Ness Ziona, Israel. FAU - Mevorach, Dror AU - Mevorach D AD - Enlivex Therapeutics Ltd., Ness Ziona, Israel. AD - Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. AD - The Institute of Rheumatology-Immunology-Rheumatology, The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center and Hebrew University-Hadassah Faculty of Medicine, Jerusalem, Israel. LA - eng SI - ClinicalTrials.gov/NCT04590053 SI - ClinicalTrials.gov/NCT04513470 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230802 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - SARS-CoV-2 variants SB - IM MH - Male MH - Humans MH - Middle Aged MH - Female MH - *COVID-19/complications MH - SARS-CoV-2 MH - *Respiratory Distress Syndrome MH - Inflammation MH - Apoptosis PMC - PMC10433372 OTO - NOTNLM OT - ARDS OT - COVID-19 OT - apoptotic cells OT - cytokine storm OT - macrophage reprogramming COIS- PH received honoraria from Enlivex Ltd as a consultant. DM is the founder and the Chief Scientific Officer of Enlivex Therapeutics Ltd. YS, BR, LB and OH are employed by 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 a potential conflict of interest. EDAT- 2023/08/21 06:42 MHDA- 2023/08/22 06:42 PMCR- 2023/08/02 CRDT- 2023/08/21 04:51 PHST- 2023/06/19 00:00 [received] PHST- 2023/07/17 00:00 [accepted] PHST- 2023/08/22 06:42 [medline] PHST- 2023/08/21 06:42 [pubmed] PHST- 2023/08/21 04:51 [entrez] PHST- 2023/08/02 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1242551 [doi] PST - epublish SO - Front Immunol. 2023 Aug 2;14:1242551. doi: 10.3389/fimmu.2023.1242551. eCollection 2023.