Israeli immunotherapy company Enlivex Therapeutics said Wednesday that 16 severe and critical COVID-19 patients who received its experimental treatment had survived a 28-day Phase II clinical trial period.
Two of the patients, who were critical cases at the start of the trial when they received the company’s Allocetra treatment, were still in intensive care and on ventilators at the end of the trial.
The other 14 patients recovered, were discharged from the hospital by the end of the trial and were reported to be healthy. The average duration of hospitalization after receiving Allocetra, for those who were discharged, was 5.3 days, the company said.
At the start of the trial, nine of the patients were in severe condition and seven were critical.
The company did a preliminary trial of five COVID-19 patients last fall. All of those patients, who were in severe to critical condition when they received the drug, were released from the hospital with an average stay of under 10 days after getting Allocetra.
The two trials together, therefore, had a mortality rate of zero percent in 21 severe to critical cases, although the fate of the two patients still in the ICU remains uncertain.
The majority of patients in both trials had preexisting risk factors including obesity and hypertension, the company said.
In the Phase II trial, 12 of the patients were at Hadassah Medical Center in Jerusalem, three at Barzilai in Ashkelon and one at Ziv in Safed. The first trial was held at Hadassah.
Following the successful Phase II trial, the company will submit the data for review by regulators later this month in the hopes of using the drug widely for the treatment of severe and critical COVID-19.
Allocetra treats the over-response of the immune system and inflammatory response that is sometimes seen in COVID-19 patients, called a cytokine storm. The phenomenon can cause severe immune system attacks on the body’s own organs, leading to organ failure and sometimes death.
Cytokine storms are difficult to treat because they are complex responses involving multiple biological systems reacting, and interacting, at the same time. Cytokines are proteins used in cell signaling that summon immune cells during an immune response.
Allocetra uses the body’s own regulation mechanisms to tamp down the storm without hampering the immune system, the company said. The treatment infuses billions of early apoptotic cells, or dying cells, into the bloodstream.
Macrophages and dendritic cells, the body’s first responders, feed on these apoptotic cells, releasing fewer cytokine alert signals and calming the storm.
The company first demonstrated the drug’s safety in treating a small group of sepsis patients.
Enlivex, based in Ness Ziona, is a clinical stage immunotherapy drug company, focused on balancing the immune system. It was founded in 2005. Allocetra is the firm’s leading treatment and the furthest along in trials.
Sepsis, identified by the World Health Organization (WHO) as a global health priority, has no specific proven pharmacologic treatment other than appropriate antibiotics, intravenous fluids, vasopressors as needed, and possibly corticosteroids.1-4 The reported death rate from sepsis in hospitalized patients ranges between 30% and 45%.5-10
In sepsis, binding of either pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) to complement, toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)like receptors, retinoic acid-inducible gene (RIG)like receptors, mannose-binding lectin, and scavenger receptors, among others, induces a complex intracellular signaling system with redundant and complementary activities.11,12
Triggering of innate immunity assures a common response pattern, regulated by the level and variation of the repertoire of PAMPs and DAMPs, and the resulting signaling pathways that are activated. This sequence of events leads to the expression of several common classes of genes that are involved in inflammation, adaptive immunity, and cellular metabolism.
The complementary nature of the pathways explains the overlapping yet unique early inflammatory response to common Gram-negative and Gram-positive bacterial, fungal, and viral infections, as well as tissue injury.
Interestingly, and as summarized recently, apoptotic cells in general, and Allocetra-OTS (Enlivex Therapeutics Ltd, Nes-Ziona, Israel) in particular, were shown to have a modulating effect on cytokine storms, with downregulation of both anti- and pro-inflammatory cytokines derived from PAMPs and DAMPs, in both animal and human in vitro models.13
Therefore, the current study was designed to examine the safety and the possible beneficial immuno-modulating effects of apoptotic cells (Allocetra-OTS, Enlilvex Therapeutics Ltd., Nes-Ziona, Israel) administered to patients presenting with sepsis.
In a previous dose-escalating clinical study enrolling patients undergoing bone marrow transplantation who had an elevated cytokine profile, matched apoptotic cells were shown to be safe and efficacious with a dose-dependent effect starting at 140×106 cells/kg.14
This dose, administered in either one or two treatments, was chosen for the current study. In addition, the outcome of study subjects in this safety trial were compared to historical matched controls to compare outcomes at 28 days.
Alloctera-OTS preparation
Enlivex Therapeutics Ltd. has developed a product named Allocetra-OTS based on the known activity of naturally occurring apoptotic cells to induce a pro-homeostatic state for both macrophages and dendritic cells (DCs)13,14,16-18 that contributes to maintenance of peripheral homeostasis of almost all immune-triggered mechanisms in sepsis.
Allocetra-OTS is composed of irradiated non-HLA-matched mononuclear enriched leukocytes containing at least 40% early apoptotic cells, in the form of a liquid suspension that is administered intravenously (IV).
Discussion
Apoptotic cells have immunomodulatory functions via their interaction with macrophages and dendritic cells, and their administration was suggested to be used as a potential therapeutic intervention.13,14,31-33 Allocetra-OTS preparation is unique, with an emphasis on early apoptosis (i.e. apoptotic cells are Annexin V+ propidium iodide−) to avoid any effect from necrotic cells.
Although not all the molecular events underlying the potential immune-regulating function of apoptotic cells are clear, changes in macrophages and dendritic cells towards a homeostatic phenotype have been investigated by several authors and implicated in apoptotic cell-mediated immune modulation (reviewed by13,32,33).
Local administration of apoptotic cells has been used to attenuate both bleomycin- and lipopolysaccharide (LPS)-induced lung inflammation, with reduced neutrophil recruitment into the lung, enhanced phagocytosis by alveolar macrophages, and reduced pro-inflammatory cytokine production.34
Infusion of apoptotic cells 24 hours after initiation of sepsis has also been shown to protect against mortality in a mouse model of sepsis, with reduced pro-inflammatory cytokine and neutrophil recruitment into organs.35
Many of the measured cytokines/chemokines/immune-modulators were proven to be pathogenic in sepsis and septic shock; however, single targeting of cytokines did not ameliorate sepsis in many trials using anti-TNF, anti-IL-1β, and other cytokines in sepsis.36
Interestingly, and as suggested elsewhere,37 anti-inflammatory cytokines are also elevated early in the course of sepsis. This supported the notion that secretion of pro- and anti-inflammatory mediators in septic shock occurs as a simultaneous immune response program initiated early in the course of the disease,38 and in severe sepsis, the IL-10/lymphocyte ratio was significantly correlated with the APACHE II score and strongly predicted 28-day mortality.39
Apoptotic cell infusion represents a more holistic approach, leading to rebalancing of all pro- and anti-inflammatory cytokines and chemokines, growth factors, and other immuno-modulating agents, and reprogramming of monocytes/macrophages and dendritic cells.13
In the first few days of clinically apparent infection, there is an innate immune response in all patients. Gene expression studies have shown that transcripts from sepsis and severe viral infections involve pathways associated with signaling through TLRs, IL-27, IL-12, IFN-γ, type I IFN-inducible transcripts, and the JAK-STAT pathway that are overabundant in the acute phase and remain elevated until defervescence occurs and may lead to endothelial dysfunction.40
The mechanism through which cytokines such as TNF might mediate endothelial dysfunction are not clear, though changes in the integrity of inter-endothelial cell junctions is a possible cause. Most permeability-inducing factors bind to endothelial cell plasma membrane receptors, activate heterotrimeric G proteins, and cause an increase in intracellular Ca2+.
This results in myosin-driven endothelial contraction and opening of tight junctions. In some viral diseases, increased capillary permeability occurs when viremia is in steep decline and serum cytokine concentrations are at or near their peak levels.40
In addition, pathogen-induced lung injury can progress into acute lung injury or its more severe form, acute respiratory distress syndrome (ARDS), as seen with sepsis and SARS-CoV or influenza virus infections.
To further evaluate apoptotic cell effect a randomized-controlled trial is needed, but these results may reflect a novel and safe mechanism for treatment of sepsis as well as diseases associated with cytokine storm such as flu complications, acute lung injury and acute respiratory distress syndrome as seen in SARS-CoV and influenza virus infections,41 CAR-T therapy,42,43 and the recently described COVID-19.44,45
REFERENCE LINK: https://www.medrxiv.org/content/10.1101/2020.12.03.20242586v2.full
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