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. 2023 Aug 2:14:1242551.
doi: 10.3389/fimmu.2023.1242551. eCollection 2023.

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

Peter Vernon van Heerden  1 , Avraham Abutbul  2 , Ahmad Naama  3 , Shlomo Maayan  4 , Nassar Makram  4 , Akiva Nachshon  1 , Kamal Abu Jabal  5 , Oren Hershkovitz  6 , Lior Binder  6 , Yehudit Shabat  6 , Barak Reicher  6 , Dror Mevorach  6   7   8
Affiliations

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

Peter Vernon van Heerden et al. Front Immunol. .

Abstract

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.

Keywords: ARDS; COVID-19; apoptotic cells; cytokine storm; macrophage reprogramming.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Mortality rates of COVID-19 patients at Hadassah Medical Center. The mortality rates of (A) all COVID-19 patients (n = 4,177) or (B) only critical COVID-19 patients (n = 197) that were hospitalized at the Hadassah Medical Center during the time of the studies.
Figure 2
Figure 2
Blood counts of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line); blood samples were analyzed for (A) white blood cells (WBCs), (B, C) neutrophils, (D, E) lymphocytes, (F) neutrophil/lymphocyte ratio (NLR), and (G) platelet counts at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 3
Figure 3
Acute phase and cardiac markers of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Blood samples were analyzed for (A) CRP, (B) ferritin, (C) D-dimer, (D) CPK, and (E) creatinine at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 4
Figure 4
Liver markers and enzymes of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Blood samples were analyzed for (A) AST, (B) ALT, (C) alkaline phosphatase (ALP), (D) total bilirubin, and (E) LDH at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 5
Figure 5
Pro-inflammatory cytokines of COVID-19 patients treated with Allocetra-OTS. Severely/critically ill COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Serum samples were analyzed for (A) TNF-α, (B) IL-1β, (C) IL-2, (D) IL-6, (E) IL-18, (F) IFN-α, (G) IFN-β, and (H) IFN-γ cytokine concentration at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 6
Figure 6
Anti-inflammatory cytokines of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Serum samples were analyzed for (A) IL-10, (B) IL-1Ra, (C) IL-2Rα, (D) TNFR-1, and (E) IL-4 cytokine concentration at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 7
Figure 7
Chemokines of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Serum samples were analyzed for (A) MCP-1, (B) MIP-1α, (C) IP-10, (D) IL-8, (E) MCP-3, and (F) MIG (CXCL9) chemokine concentration at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
Figure 8
Figure 8
Hematopoietic growth factors (HGFs) of COVID-19 patients treated with Allocetra-OTS. Severe/critical COVID-19 patients from studies NCT04513470 (gray symbols) and NCT04590053 (black symbols) were treated with Allocetra-OTS on day 1 (red dotted line). Serum samples were analyzed for (A) G-CSF, (B) IL-7, and (C) GM-CSF HGF concentration at the indicated timepoints. The first blood sampling for each patient was taken before IV administration of Allocetra-OTS. Data are shown as average ± range.
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