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The excessive inflammatory response seen in the most serious cases of Covid-19, along with shortages of ventilators, has caused a healthcare crisis in many countries around the world. Could cell therapy provide an answer to this dilemma? Most people who become infected with Covid-19 experience symptoms such as a dry cough and mild fever, and recover without medical care. But around 14% develop more severe symptoms including pneumonia and shortness of breath. Approximately 5% of patients with severe cases of Covid-19 have to be put on a ventilator due to acute respiratory distress syndrome (ARDS). The patients’ lungs become severely inflamed, causing fluid to seep into the tissue from nearby blood vessels, making breathing increasingly difficult. Some of these patients can go on to develop septic shock and multi-organ failure, with almost half dying after reaching this stage. This respiratory failure in Covid-19 is linked to an excessive immune activation that causes a ‘cytokine storm’ where the levels of inflammatory immune proteins go dangerously high. This overreaction of the immune system was also seen in SARS and MERS patients in earlier epidemics -- both of which are also coronaviruses. While ventilators can help to keep these patients alive, recent shortages of this life-saving equipment in some countries have made it crucial to minimize the time spent on the machines. Cell therapy has shown promise for treating ARDS, which (even before Covid-19) affected 500,000 people a year across Europe, the US, and Japan. The US-based cell therapy biotech Athersys -- presenting at a webinar held by the Alliance for Regenerative Medicine last week -- has been developing a cell therapy called Multistem that it claims “decreases the adverse results of inflammation, while activating reparative immune cells.” Multistem is an ‘off the shelf’ cell therapy derived from bone marrow donations. Eric Jenkins, Senior Medical Director and Head of Clinical Operations at Athersys, explained that the cells are not mesenchymal stem cells -- adult stem cells traditionally found in bone marrow and other connective tissue -- but are a different type of adult bone marrow stem cell called multipotent adult progenitor cells, and have greater growth potential in the lab. Athersys’ cell therapy is being trialed for reducing the damaging inflammation seen in stroke patients. It was also being developed for the treatment of ARDS even before the Covid-19 pandemic. The company recently reported results from a completed a phase I/II study testing Multistem in 30 patients (20 treated with cell therapy; 10 with placebo) with ARDS in the US and UK. The study showed that treatment with the cell therapy reduced mortality from 40% to 25% in these very sick patients. “We believe that, in these vulnerable patients, Multistem can effectively interrupt this pathological cycle and promote an immunologic transition that leads to patient recovery,” emphasized Jenkins. Based on these results, and with support from the Biomedical Advanced Research and Development Authority in the US, Multistem is now being tested in a phase II/III trial for the treatment of ARDS in Covid-19 patients. Athersys is additionally collaborating with Japanese biotech Healios, which is also currently testing Multistem in its own study in Covid-19 ARDS patients. Another company diverting its expertise to the treatment of ARDS in Covid-19 patients is Israeli biotech Pluristem Therapeutics. Earlier this month, Pluristem announced it had secured €50M in non-dilutive funding from the European Investment Bank to fund its Covid-19 therapy development. Pluristem develops cell therapies made from placental cells. Its most advanced candidates target critical limb ischemia, where reduced blood flow often leads to amputation or death, and muscle damage after hip fracture. “We have favorable safety profile and efficacy data from hundreds of patients treated worldwide in these two indications,” commented Racheli Ofir, VP Research & Intellectual Property at Pluristem, which participated in the same webinar as Athersys. Similar to Athersys’ therapy, Pluristem’s cells are delivered ‘off the shelf’ and also have the ability to regulate the immune system to potentially calm the excessive immune activation seen in Covid-19 ARDS patients. The company announced in March that it planned to work with the Charité University of Medicine in Berlin to develop a cell therapy to treat these patients. Since March, Pluristem has treated a number of patients with Covid-19-induced ARDS in Israel and in the US as part of a ‘compassionate use’ program. The company followed up seven patients in Israel and one in the US for 28 days after treatment with the cell therapy. Pluristem found that 87.5% survived, 75% no longer needed ventilation and 62.5% had been discharged from hospital. The company now plans to start a phase II trial of its therapy in the US, which has been cleared by the FDA, and is waiting for clearance to start a trial in Germany and Italy. These are just two examples of companies working to develop effective treatments for the severe symptoms seen in some Covid-19 patients. Another advanced example in clinical development is a cell therapy developed by the Australian biotech Mesoblast, which began a phase II/III trial this month. All in all, the Alliance for Regenerative Medicine is currently tracking 24 ongoing clinical trials and an additional 25 preclinical studies for cell therapies against Covid-19. Although these therapies seem to offer hope for the minority of patients who become seriously ill with Covid-19, it’s important to note that many of the studies that have been carried out so far are very small and may not represent efficacy on a larger scale. In the circumstances of the current pandemic, both Jenkins and Ofir think they will be able to recruit full cohorts for their respective clinical trials fairly quickly. But it is likely that we will have to wait for a few more months at least to find out whether these cell therapies can be effective on a larger scale for patients with ARDS. If they do work out, they could provide an extra line of defense in countries heavily affected by the Covid-19 pandemic, as well as any subsequent waves in the near future. Images from E. Resko and Shutterstock

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