Making Headway in the Quest for COVID-19 Cell Therapies

With the SARS-CoV-2 virus now widespread around the globe, scientists across many disciplines are racing to develop therapies for COVID-19 – a disease which has disrupted our world. Vaccine research continues, and a wide range of potential treatments are being explored, including the repurposing of small molecules and de novo design of drugs and peptides. Interest in cell-based therapies has escalated over recent decades, largely driven by a growing appreciation for the inter-individual variation that exists for many diseases and the subsequent shift towards personalized medicine.

This trend has been supported by increasing technical and manufacturing capabilities and has continued in 2020. In June, a director from the US Food and Drug Administration (FDA) said their clinical team was “stretched” trying to deal with the COVID-19-related growth. In the same month there were more than 1000 cell therapies in the pipeline, 25 of which were available in the market. Increasing commercial investment suggests expectations of the industry are high, and it is hoped cell therapies will be available to treat a wide range of diseases in the near future. Faced with a global pandemic, we explore the following questions: can cell therapies help alleviate the symptoms of COVID-19? What strategies are being employed?

Buyer beware: a note on cell therapy quality control

The cell therapy field has seen remarkable progress in recent years, including advances in stem cell programming and upscaling production capabilities. Unfortunately, fraudulent individuals have taken advantage of the enormous potential of this field, with unregulated, dishonest “stem cell clinics” making false claims and selling illegal and harmful treatments (some of which have led to serious infections, blindness and death). Many biologists, clinicians and scientific societies believe that haphazard use of the poorly-defined term “mesenchymal stem cells” has contributed to unwarranted hype by making it easier for those at the bottom of the stem cell barrel to sell false treatments. Corruption has also reared its head in academia; in 2018, 31 papers coauthored by a high-profile researcher were retracted, following the identification of manipulated and fabricated data relating to cardiac stem cells that could supposedly regenerate damaged heart muscle.

For the honest majority in the field, these incidents are a major source of frustration and concern, and professional organizations have issued statements opposing the marketing of unfounded stem cell treatments for COVID-19, including Euro Stem Cell, the International Society for Cell and Gene Therapy and the International Society for Stem Cell Research.

Cell therapies are living products with a high level of complexity and run the risk of being rejected by the host’s immune system. Navigating the complexities of cell therapy quality control is a challenging task, as there is no “one-size-fits-all” set of procedures. Instead, scientists must find ways to demonstrate critical quality attributes deemed important by regulatory authorities, such as identity, sterility, genetic fidelity and stability, viability and potency (in the case of induced pluripotent stem cells (iPSCs)).

The COVID-19 pandemic generated a massive flurry of clinical trials, the majority of which are expected to produce a low level of evidence. Maintaining a comprehensive global register of clinical trials is difficult, and half of non-US studies are estimated to not be registered with the widely used database ClinicalTrials.gov. The authors of a research letter to Jama Internal Medicine highlighted the implications of these challenges and wrote that “rapid dissemination of studies with low-quality evidence can influence public opinion, government actions and clinical practice in potentially harmful ways”. Innovative solutions have been employed to help scientists keep track of global trial data, including artificial intelligence-based methods which capture studies not listed in trial registries, and living systematic reviews that are updated to reflect emerging evidence.

Examples of experimental cell therapies for COVID-19

In the sections below, we delve into a selection of potential cell-based therapeutic approaches and summarize others in Table 1.

Table 1. Examples and rationale of cell therapy approaches for COVID-19

Type of cell therapy	Rationale	Proposed benefits
Convalescent plasma therapy	Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2.	Suppress the virus and modify the inflammatory response.
Immunotherapy, including the transfer of T cells from convalescent donors and engineered NK cells	Goal is to develop cells that will help the host modify various inflammatory/immune responses.	Reduce overall disease severity.
Mesenchymal stem cells/medicinal signaling cells and their derivatives	Potential immunomodulatory effect via secretion of cytokines, chemokines, growth factors and extracellular vesicles, or direct interaction with immune cells.	Limit inflammation and limit lung fibrosis.
Lung stem cells (through clonal expansion or iPSC differentiation)	Alveolar regeneration.	Improve endogenous repair of damaged tissue in lungs of recovered patients suffering from alveolar damage.
Exosomes, derived from various sources e.g. T cells, amniotic fluid	Five COVID-19 exosome clinical trials have been registered.	Mechanisms unknown, despite the promising therapeutic potential of exosomes.

Convalescent plasma: the jury is still out

Early in the pandemic, a century-old treatment was proposed as a potential therapeutic option for COVID-19. The medicinal use of convalescent blood products, collected from a patient who has survived a previous infection and developed humoral immunity to the respective pathogen, dates back to the 1880s. Since then, a number of studies have indicated that convalescent plasma (CP) therapy has merit as an effective strategy, based on reports related to viral infections including the Spanish influenza, Middle East respiratory syndrome coronavirus, H1N1 and H5N1 avian flu. Whether plasma from donors who have recovered from COVID-19 can provide passive immunization to recipients remains to be seen.

At present, the NIH states there are insufficient data to recommend for or against this approach and notes serious risks related to transfusion, allergic reactions and the theoretical potential for antibody-dependent enhancement of infection. Inconclusive studies have not stopped CP being used as an experimental treatment around the world and after reading this review published in April it is easy to keep an open mind. In the same month, the FDA issued guidance on the emergency use of CP for people with serious or immediately life-threatening COVID-19 infections, allowing access if their GP gained authorization through the single patient emergency Investigational New Drug pathway. In the last few days, the FDA increased the availability of the experimental treatment by issuing an emergency use authorization (EUA) for investigational CP in the treatment of COVID-19, a move which allows unapproved medical products to be used in an emergency when there are no adequate, approved and available alternatives. Regardless, randomized, double-blind trials are still needed to shed light on CP therapy.

Given the many unknowns, it is unsurprising that CP therapy has attracted a great deal of skepticism. As highlighted by Antonio Bertoletti, professor in the Emerging Infectious Disease Programme at Duke-NUS Medical School: “SARS-CoV-2 preferentially infects cells in the upper respiratory tract… thinking that infused plasma is sufficient to achieve a level of antibodies that can achieve direct clearance of the infected cells in the upper/lower respiratory tract seems like a long shot.” Bertoletti notes that we just don’t know enough about the potential protection mechanisms – for CP therapy and don’t yet have a comprehensive understanding of therapeutic approaches under investigation. He also adds: “However, if they [CP approaches] demonstrate that an antibody can detect virus-infected cells and help direct natural killer cells towards the targets via antibody-dependent cellular cytotoxicity… I would be ready to accept that plasma therapy could be an answer for blocking the development of severe COVID-19 cases.”

The living systematic review of CP trials can be checked for updates on CP progress; it was last revised on July 10^th, at which point there were 98 ongoing studies evaluating CP and hyperimmune immunoglobulin (concentrated CP), 50 of which were randomized clinical trials. In general, the level of certainty for efficacy (as assessed by need for respiratory support) and safety was rated as “very low”.

Taking inspiration from immunotherapy

Strengthening aspects of one’s immune system through the use of cell therapy is not a novel concept; the last few years have been described as the decade of immunotherapy. As CAR T-cell therapy (T cells engineered with a chimeric antigen receptor) has made its way into mainstream cancer treatment, scientists have begun to ponder this question: Could immunotherapy be used to treat infectious diseases? Bertoletti addressed this concept in March as coauthor of a commentary published in the Journal of Experimental Medicine: “Challenges of CAR- and TCR-T cell-based therapy for chronic infections”, where he highlighted obstacles and explained how specific chronic infections like hepatitis B virus might benefit from this immunotherapy.

Meanwhile, infectious disease specialist Joshua Rhein, MD, assistant professor in the Medicine, Division of Infectious Diseases and International Medicine at the University of Minnesota, serendipitously found himself drawn into a trial investigating the use of natural killer (NK) cells against COVID-19. His colleague, Jeffrey Miller, MD, has spent over 20 years studying the biology of NK cells and other immune effector cells, and their use in clinical immunotherapy. Rhein was on clinical service when the first COVID-19 patient came into the hospital (who also happened to be the first COVID patient in Minnesota): “I think the project sort of fell on my lap. Jeff must have already been thinking about the application of NK cells for something outside of cancer, and he came to me with this idea”. Together with their industry partner, the team at the University of Minnesota have developed an experimental therapy using NK cells. “The very early data from China was showing us that the NK cells of patients with COVID become depleted, as had the whole lymphocyte line. Not only that, but the more significant the depletion, the more severe the disease is,” explains Rhein.

NK cells are a subset of lymphocytes that kill their cellular targets (e.g. cancerous or virus-infected cells) through a range of methods; both directly, by releasing proteins called perforins, which create porous networks in the target cell’s plasma membrane and cause it to disintegrate, and indirectly, through the activation of nearby immune cells. NK cells can also clear virus-infected cells through antibody-dependent cytotoxicity, a process that Rhein and Miller hope to enhance. The cells in their trial have been engineered with a non-cleavable Fc receptor called CD16, which delivers a potent signal to NK cells upon recognition of antibody-coated cells. Ideally, Rhein says, the NK cells will carry out two main functions, “by directly targeting infected cells. Later, this can be enhanced through the development of the patient’s own antibodies. When the non-cleavable CD16 recognizes the tail of the antibody, the NK cell goes into activation, or increased activation.” This month, the first COVID-19 patient received an infusion, which marks the beginning of a dose escalation protocol, with patients receiving higher doses as tolerance is demonstrated.

Medicinal signaling cells: rationale for their therapeutic use against COVID-19

Globally, 55 registered COVID-19 studies are investigating (or plan to investigate) the potential therapeutic application of “mesenchymal stem cells”, a term with a “messy” past. Arnold Caplan, who coined the term “mesenchymal stem cells” (MSCs) nearly 30 years ago has long been calling for the term to lose its stem cell nomenclature, because it is scientifically and therapeutically misleading. Originally, MSCs received their name for their in vitro multipotency and clonability. However, it is now understood that MSCs are not true stem cells as they do not undergo asymmetric cell division (ACD), whereby two cells are produced: one copy of the original stem cell, and one that is programmed to differentiate into a non-stem cell fate. Many believe that the term “stem cell” implies MSCs will function as progenitors for tissues, directly converting into the injured tissue in question – which is not the case.

Contention aside, however, the cells are still regarded to have potential therapeutic value. “Medicinal signaling cells” has been suggested as a more appropriate alternative as it reflects their paracrine capacity. The National Institutes of Health (NIH) describes MSCs (using their original name) as “investigational products that have been studied extensively for broad clinical applications in regenerative medicine and for their immunomodulatory properties.” It is hypothesized that MSC therapeutics have the potential to alleviate severe COVID-19 and accelerate the recovery of critically ill patients by eliciting beneficial effects on immunomodulation, tissue repair and organ protection. MSCs have been shown to have possible anti-fibrotic effects and have induced functional changes of monocytes/macrophages, dendritic cells, T cells, B cells and NK cells. Interestingly, immunomodulatory properties have been recorded in apoptotic, metabolically inactivated and fragmented MSCs. In the setting of COVID-19 it is hoped that MSCs will help dampen the intense inflammatory response (“cytokine storm”) seen in advanced stages of disease.

Safety first, immunopathogenesis studies needed

As with all cell therapies and immunotherapy interventions, the priority is to ensure patient safety. For Rhein’s group, this means selecting the appropriate patient group for the trial; those who are sick enough to benefit from an experimental therapy, but not too sick as there is a concern that the NK cells could push the patient towards a hyperinflammatory state. A number of factors are taken into consideration, including respiratory status and guidance from inflammatory markers. “Some of our enrolment criteria is based on C-reactive protein and IL-6… I think there’s more and more evidence of this in COVID that you can really predict which patients are at a high risk for developing this hyperinflammatory state,” explains Rhein.

As Bertoletti notes, we need to increase our knowledge of the immunopathogenesis of SARS-CoV-2 infection: “Are severe diseases caused directly by the virus quantity or, as it seems, are they more related to excessive inflammatory conditions? Without some clear understanding of such fundamental knowledge of immunopathogenesis of viral diseases is hard to predict what immunotherapy can work.”

Michele Wilson is a freelance science writer for Choice Science Writing.