As the race for remedies to COVID-19 continues, basic questions about the virus’s pathology and virulence remain unanswered. While much about the disease is unknown, this much is clear: COVID-19 is accelerating medical innovation, especially in the field of cell therapies.
Researchers with CellTrials.org report that well over 100 clinical and preclinical trials have been registered to test the efficacy of cell therapies to target complications from COVID-19 infection. While vaccine development commands the bulk of media attention, other companies are working on cell therapies aimed at treating COVID-19.
All eyes on ARDS
Most of the trials underway focus on therapies that modulate the immune response in patients with Acute Respiratory Distress Syndrome (ARDS). ARDS is a severe complication of COVID-19 and one of the leading causes of death from the virus. It is caused by the buildup of fluid in the lungs and a common manifestation of cytokine storms.
When cytokines are released too quickly, immune cells can attack healthy tissues, leading to blood clots, organ damage and death. Cytokine storms have been linked to deaths in pandemics before, including the 2003 SARS epidemic and the H1N1 swine flu.
With no effective pharmaceutical or biological treatments currently available, ARDS represents a major area of unmet medical need — and a key concern for cell and gene therapy developers. Many therapies currently in development are exploring how mesenchymal stem cells (MSCs) and other stromal cells could trigger immune responses to fight ARDS.
For example, Cleveland-based Athersys completed an exploratory Phase 2 trial in the United Kingdom and the United States. In the trial, 20 patients with moderate to severe ARDS were given a single infusion of MultiStem®, a stem cell-based treatment developed from multipotent adult progenitor cells, within four days of being diagnosed.
Patients receiving the treatment experienced a significant reduction in mortality, increased pulmonary function and increased ventilator-free days. Moreover, 45% of patients treated with MultiStem were off mechanical ventilation by day seven of the trial, versus just 20% who received a placebo. Encouraged by these findings, Athersys is currently recruiting for a Phase 2/3 study of MultiStem. The study will enroll approximately 400 patients with complications related to COVID-19.
Researchers at the Cedars-Sinai Smidt Heart Institute and Capricor Therapeutics reported equally promising results earlier this year. From March 25 to April 28, six COVID-19 patients with ARDS received infusions of Capricor’s CAP-1002. The therapy uses cardiosphere-derived cells to induce regeneration.
The patients included five men and one woman between 19 and 75 years of age. All six patients survived and the results were published in May in the journal Basic Research in Cardiology. It was one of the first peer-reviewed papers exploring the use of cell therapy to encourage helpful immune responses in critically ill COVID-19 patients. Capricor is continuing that research with a Phase 2 study of patients who have a confirmed case of COVID-19 and require supplemental oxygen.
Other companies are exploring similar approaches. Pluristem Therapeutics, based in Haifa, Israel, is enrolling patients in a U.S.-based Phase 2 study. Its preliminary results from a compassionate use program found that infusions of PLX cells — allogeneic mesenchymal-like cells — can coax patients’ immune systems to reverse the effects of ARDS. Preliminary results are expected in May 2021.
Mesoblast Ltd., of Melbourne, Australia, has initiated a Phase 3 trial of 300 ventilator-dependent patients with the goal of evaluating the potential of MSCs “to increase survival in management of COVID-19 induced ARDS.” The first patients were dosed in May with Mesoblast’s allogeneic cell therapy, remestemcel-L, after the company reported promising results from an earlier compassionate use program. The trial surpassed 50 percent enrollment in October; preliminary results from the Phase 3 trial are expected in April 2021.
Additionally, Mesoblast is running a trial to assess safety and efficacy of remestemcel-L for children and adolescents suffering from multisystem inflammatory syndrome. The condition, which is known to be associated with COVID-19, causes inflammation of different body parts.
And NantKwest, a California-based cellular therapy developer, is studying whether its bone marrow-derived allogeneic BM-Allo.MSC can modulate the immune response in COVID-19 patients. Be The Match BioTherapies® is partnering with NantKwest to support the company’s ongoing Phase 1b clinical trial. Results are expected in June 2021. NantKwest and ImmunityBio are also testing a potential vaccine and dosed the first patient in a Phase 1 trial in October.
The road ahead
The clinical trial pipeline for cell therapies continues to fill. For instance, in early November, Agenus, an immune-oncology company based in Lexington, Mass., dosed its first COVID-19 patient with agenT-797. The iNKT allogeneic cell therapy is designed to treat moderate to serve COVID-19 symptoms by clearing the virus, dampening inflammation and preventing reinfection. Similar updates are a daily occurrence as the biotech industry races to develop new therapies capable of reducing mortality and facilitating recovery.
But the development of therapeutics and associated clinical studies takes time, even under ideal circumstances.
One of the chief challenges for the development of cell therapies during a global pandemic is the availability of donor cells. To address this issue, nearly half (48%) of the registered clinical trials use cells from perinatal sources, according to CellTrials.org co-founders Frances Verter, Ph.D., and Pedro Silva Couto.
For instance, biotech companies, such as Houston-based Cellenkos and Galway, Ireland-based Orbsen Therapeutics, are engaged in trials to treat ARDS in COVID-19 patients with cells derived from cord blood. Cord blood has the benefit of not being dependent on adult donors who need to travel to an apheresis center to donate their cells.
Another concern is the pace of development, which slowed dramatically during the height of the pandemic. Researchers working on clinical trials have cited staffing shortages, a dearth of willing patients and other issues causing delays in their ability to test the most promising experimental drugs and treatments.
While some of this backlog is clearing, the U.S. Food and Drug Administration says it will still take months for regulators to catch up. Similarly, it will take months — and in some cases years — for the cell therapies under study to yield approved treatments.
But as Eric Jenkins, Senior Medical Director and Head of Clinical Operations at Athersys, noted recently, the sense of “desperation and urgency in the face of unmet therapeutic need” that COVID-19 is causing is no reason to cut corners on scientific and regulatory processes.
Furthermore, because many of the therapies being studied today are not virus-specific, their usefulness will outlive the current coronavirus, and might even help fight a future global pandemic. That’s an outcome worth waiting for.