Apoptotic cells for treatment of acute respiratory distress syndrome associated with COVID-19

Peter Vernon van Heerden, Avraham Abutbul, Ahmad Naama, Shlomo Maayan, Nassar Makram, Akiva Nachshon, Kamal abu Jabal, Oren Hershkovitz, Lior Binder, Yehudit Shabat, Barak Reicher, Dror Mevorach

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number1242551
JournalFrontiers in Immunology
StatePublished - 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 van Heerden, Abutbul, Naama, Maayan, Makram, Nachshon, abu Jabal, Hershkovitz, Binder, Shabat, Reicher and Mevorach.


The authors declare that this study received funding from Enlivex Therapeutics Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

FundersFunder number
Enlivex Therapeutics Ltd


    • ARDS
    • COVID-19
    • apoptotic cells
    • cytokine storm
    • macrophage reprogramming


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