The Coronavirus Pandemic: A Pitfall or a Fast Track for Validating Cell Therapy Products?

The serious consequences of the COVID-19 pandemic have prompted a global initiative to develop effective therapies that can lessen disease severity in infected patients, particularly those with severe respiratory disease. Cell-based approaches, primarily using mesenchymal stromal cells (MSCs), have demonstrated an acceptable safety profile in patients with non-SARS-CoV-2–related acute respiratory distress syndrome (ARDS) in the limited currently available information [1]. However, whether these therapies are effective for treating respiratory virus-induced ARDS, including that resulting from SARS-CoV-2, is unknown [1]. This is despite several recent case reports and uncontrolled case series suggesting potential efficacy [2,3]. Regardless, there are an increasing number of both academic and industry-sponsored trials of cell-based therapies for COVID-19 patients initiated over the past several months. Most are investigating use of MSCs, but some are investigating MSC-derived products including extracellular vesicles (EVs) and some are utilizing other cell types. In parallel, there has been a worrisome increase in the number of businesses offering unproven and untested cell-based therapy approaches in uncontrolled and unregulated settings [4]. This creates a potentially dangerous situation for patients, families, and caregivers in often desperate situations.

An overview of the rationale, preclinical data, and clinical experience of cell-based therapy in non-COVID–related ARDS provides a strong platform underlying legitimate investigations. There is a wealth of preclinical data in both small and large animal models as well as in explanted human lungs in which either systemic or direct airway administration of MSCs mitigates experimentally induced acute lung injuries resulting from bacteria or bacterial product, for example gram-negative bacterial endotoxin, administration [5,6]. The postulated mechanisms largely focus on paracrine actions of the administered MSCs, including release of anti-inflammatory cytokines, antibacterial peptides, and EVs that mitigate inflammation in the setting of acute lung injuries (Fig. 1) [7]. These encouraging results have provided a basis for the growing number of academic and industry-sponsored investigations of systemically administered MSCs in (non-COVID) ARDS patients [1]. While these studies have uniformly demonstrated a good safety profile, there remains uncertainty about potential efficacy. One major academic-based trial did not demonstrate clinical efficacy [8], whereas improvement in clinically relevant endpoints, including increased ventilator-free and ICU-free days and decreased 1 month mortality, was suggested in one major industry trial [9]. However, neither of these trials have specifically targeted patients with respiratory virus-induced ARDS. Further, there are only a small number of preclinical studies in models of respiratory virus infection, and these all involve influenza rather than coronavirus. Notably, there were contrasting results of efficacy in these studies, possibly related to the type of influenza (swine vs. avian) infection utilized. This further adds to uncertainty about whether MSC or other cell or cell product administration will have specific efficacy in SARS-CoV-2–induced respiratory failure. There are almost no available clinical data with respect to MSC administration in other types of respiratory virus infections with only a case report in a patient with H1N1 flu-related ARDS (allogeneic bone-marrow-derived MSCs) [10] and a case series after H7N9 flu infection (allogeneic menstrual blood-derived MSCs) [11].

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FIG. 1.

Overview of MSC properties relevant for potential use in COVID-19–related severe respiratory disease.

A recent search (November 2020) of the NIH clinical trial database and the World Health Organization-International Clinical Trial Registry Platform (WHO-ICTRP) revealed >3,787 recently registered clinical trials for COVID-19. Among these are 154 cell and gene therapy-based trials worldwide, with most registered in China (41) and the United States (36). Most of these utilize MSCs or their secreted products, including EVs or conditioned media. In a previous comprehensive review, we had presented an exhaustive summary of ongoing studies registered in the Chinese Clinical Trial Registry (chictr.org.cn) also accessible from the WHO-ICTRP [1]. With the continued spread of the virus, we complement that information with an updated list of trials with investigational new drug (IND) clearance from the U.S. Food and Drug Administration (US-FDA) (Table 1). Notably, a wide range of protocols with allogeneic MSCs of different origins, different doses, and different dosing strategies are being utilized. The dose of injected cells ranges from 0.5 to 2 × 10⁶ cells/kg or the equivalent in a predefined infusion dose. The number of injections varies between a single dose and up to three doses separated between 3 and 5 days with one trial utilizing up to 4 separate doses. Importantly, there are a wide range of patient groups being targeted, including those with mild or moderate disease in addition to those with severe disease. A variety of enrollment designs are being utilized including emergency and compassionate use, with only a small proportion of trials using a randomized, double-blinded placebo control format. Also, autologous MSCs derived from the patient's adipose tissue are used in three registered trials. It is unclear whether the cells were obtained before infection through adult stem cell banking or harvested after infection. In two trials, MSCs are being used for prophylaxis not only in asymptomatic COVID-19 patients but also in healthy individuals at high or very high exposure risk of contracting COVID-19. While the majority of investigations are utilizing modified MSCs, one industry trial is evaluating the safety and feasibility of MSCs RNA engineered to secrete a combination of DNases (Table 1). Further, although there is a less robust mechanistic and preclinical platform, at least seven investigations are utilizing other cell types, including cytotoxic T cells (CTLs), dendritic cells (DCs), primary natural killer cells (NKs), and induced pluripotent stem cell (iPSC)-derived NK cells already being used to treat cancer patients [12]. There is a paucity of direct evidence for the protective or pathological role of NK cells in the response to SARS-Cov-2 infection. In the context of nonrespiratory viral infections by human immunodeficiency virus (HIV) and hepatitis C virus (HCV), NK cells appear to prevent T cell-mediated autoimmunity through their cytotoxic properties [13]. However, NK cells are one of the main producers of the proinflammatory mediator interferon gamma (IFN-γ); hence, they may be involved in the induction or perpetuation of inflammation-mediated lung injuries, and subsequent mortality associated with COVID-19 [14].

Despite the lack of preclinical information on COVID-19 or any other respiratory virus pathophysiology, there has been clearance by the FDA of an IND application for the use of NK cells in clinical testing [15]. Whether these approaches are even safe for COVID-19 patients has yet to be clarified. As such we urge the FDA and other regulatory agencies to take a careful position with respect to approving cell-based products with unclear track records in either preclinical or clinical studies in lung diseases or critical illnesses for use in COVID 19 patients.

Convalescent T cells isolated from COVID-19 patients are also being considered. Recently, SARS-CoV-2–specific T cells were shown to be polyfunctional and can be expanded from convalescent individuals. These T cells were able to target structural viral proteins, including the C-terminus of membrane protein, making them good candidate for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders [16].

Of the recent published reports and small case series from both academic and industry sources suggesting potential efficacy of systemic MSC administration in COVID-19 patients, the available data presented are either anecdotal or from incompletely presented, poorly controlled investigations [2,17]. The situation is also further complicated by lack of consensus or full understanding with respect to MSC source of origin, dose, dosing strategy, use of freshly thawed versus continuously cultured cells, and other factors involved in potential use of MSC-based cell therapies. The same holds for a recently published initial safety investigation utilizing MSC-derived EVs in which no information about the actual biological substance being administered was provided [18]. Therefore, although there may be a potential role for MSCs and other cell-based therapies in treatment of COVID-19, these need to be investigated in a rationally designed, controlled approach if safety and efficacy are to be demonstrated accurately. Importantly, in addition to legitimate peer-reviewed academic trials being conducted globally, one industry-sponsored prospective randomized, double-blinded, placebo-controlled phase 2 (intramuscular injection of placental-MSC, ClinicalTrials.gov Identifiers: NCT04389450) and two phase 3 trials of intravenously administered marrow-derived MSC-like products for severe COVID-19 have been initiated in the United States (NCT04367077 and NCT04371393). The hope is that these comparable studies will provide robust data informing the utility of systemic MSC administration for COVID-related ARDS (Table 1).

At a time of unprecedented need, it is natural for patients, families, and caregivers to seek all available options, including access to cell-based and other investigational products, even before adequate demonstration of their safety and efficacy according to regulatory approval. This should not be an excuse for opportunists to sell or advertise unproven therapies of any kind. “Compassionate use” should be conducted in the context of a clinical investigation framed by strict ethical and regulatory permissions, such as expanded access authorization, with the goal of obtaining mechanistic information wherever possible. There must be a strong stance against the rogue stem cell clinic industry, which has already begun to offer unproven therapies for COVID-19. A number of global organizations, including the International Society for Cell and Gene Therapy (ISCT) and the International Society for Stem Cell Research (ISSCR), have taken positions against this predatory behavior [19]. The FDA has recently increased oversight activities against businesses offering unproven therapies, but more regulatory oversight and action are needed [20]. These actions are necessary to develop rationale evidence-based platform for potential use of cell-based therapies both for COVID-19 and for a wider range of respiratory and other diseases potentially amenable to these advanced therapies.