key: cord-0810849-e0xy8irr
authors: Khoury, Maroun; Rocco, Patricia R.M.; Phinney, Donald G; Krampera, Mauro; Martin, Ivan; Viswanathan, Sowmya; Nolta, Jan A.; LeBlanc, Katarina; Galipeau, Jacques; Weiss, Daniel J.
title: Cell-Based Therapies for COVID-19: Proper Clinical Investigations are Essential
date: 2020-04-17
journal: Cytotherapy
DOI: 10.1016/j.jcyt.2020.04.089
sha: 1c1aff9ccfa539a96b8ea4d09d1bee1707a58e7f
doc_id: 810849
cord_uid: e0xy8irr

Abstract The serious consequences of the global COVID-19 pandemic have prompted a rapid gobal response to develop effective therapies that can lessen disease severity in infected patients. Cell-based approaches, primarily using mesenchymal stromal cells (MSCs), have demonstrated a strong safety profile and possible efficacy in patients with the acute respiratory distress syndrome (ARDS), but whether these therapies are effective for treating respiratory virus-induced ARDS is unknown. According to the WHO ICTRP and the NIH clinicaltrials.gov databases, 27 clinical investigations of MSC-based cell therapy approaches have begun in China since the onset of the COVID-19 outbreak, as well as a growing number of academic and industry trials elsewhere. Several recent published reports have suggested potential efficacy; however, the available data presented is either anecdotal or from incomplete, poorly controlled investigations. Therefore, while 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. We urge that the field proceeds by finding balance between swift experimentation and communication of results, and scientifically coherent generation and analysis of clinical data.

The number of patients infected as a result of the ongoing coronavirus disease pandemic continues to increase rapidly worldwide. Mounting data demonstrates that infection with SARS-CoV-2, the viral causative agent of COVID-19, can result in significant respiratory morbidity and mortality. [1] Severe pneumonia and the acute respiratory distress syndrome (ARDS) have been described in 14% of reported cases, and the overall fatality rate is currently estimated at ~2%. [2] However, these numbers continue to evolve as the pandemic spreads and region-specific differences in rates of infection and patient outcomes emerge. Current therapeutic approaches include aggressive standard supportive care and treatment of any other co-infections. Antiviral and immune-based approaches, such as anti-IL-6 or anti-IL-1 therapy, are also under investigation, but their safety and potential efficacy remains to be determined. 

In a recently published single-center, open-label pilot investigation conducted at the YouAn Hospital in Beijing, MSCs were administered to seven patients with COVID-19 pneumonia with differing degrees of severity, including one critically ill patient requiring ICU care. [4] MSCs were given as a single intravenous administration at a dose of 1×10 6 cells/kg body weight in a total volume of 100 mL saline at various time points after initial symptomatic presentation. As described in the report, -The window period for cell transplantation was defined as the time when symptoms were getting worse even as expectant treatments were being conducted‖. The MSCs utilized were certified by the National Institutes for Food and Drug Control of China, but no information was provided regarding tissue source or mode of manufacturing. Notably, the MSCs were assessed by RNAseq for expression of ACE2 or TMPRSS2 prior to administration, and each was found to be minimally expressed (1/12,500 cells and 7/12,500 cells, respectively). Based on this result, the MSCs were assumed to be free of COVID-19 infection. However, RNAseq results were not validated for gene (qRT-PCR) or protein expression (western blot) to confirm ACE2 or TMPRSS2 expression levels, and therefore did not rule out the possibility of false-negative results.

The seven treated patients were categorized as critically severe (n=1), severe (n=4), and -common type‖ (assumed to be mild-to-moderate disease; n=2). Three patients classified as severe received placebo (vehicle) for comparison. Patients were followed for 14 days after Similarly, limited data on circulating viral titers was presented for the critically severe patient, demonstrating that titer was persistently positive 6 days after MSC administration, becoming negative by 13 days. However, no quantitative data were presented and no other information was presented for any of the other patients.

The authors appreciate that under the current pandemic conditions it may be difficult to recruit patients for placebo controlled trials and that patient randomization is complicated by the fact that multiple agents are being utilized and/or investigated. They also appreciate the need for rapid publication of results from pilot clinical trials in COVID-19 patients. In lieu of these limitations, interpreting the impact of the clinical data reported by Leng et al. [8, 9] these data were limited and in some cases unclear in the analyzed case report. Consequently, while the authors speculate about the mechanism of MSC action in COVID-19 patients and their effects on the immune system, definitive results will require large-scale, randomized controlled trials to delineate mode(s) of action, which may be disease specific. Importantly, while the authors did not discuss potential patient targeting for MSC administration, it is important to However, no details on the deaths, including cause and timing related to either infusion or to overall clinical course, were provided. Moreover, no other outcome measures now considered standard for evaluating new potential therapies in intubated, mechanically ventilated patients-such as ventilator-free days, length of ICU stay, or length of hospital stay-were reported. Limited long-term follow-up data was presented for a small number of treated patients, and appeared to indicate no difference in long-term sequelae observed in ARDS survivors compared to those reported in the literature. Baseline laboratory data, including complete blood count and measures of renal, liver, cardiac, and coagulation functions, were comparable, except for a higher circulating procalcitonin level in the control group (perhaps suggestive of secondary or co-occurring bacterial superinfection).

However, no information on other infections was provided. There were many differences in laboratory values between treated and control patients at discharge; however, no information as to the definition of discharge was provided, nor was any other relevant information about clinical course reported. Based on these findings, the authors concluded that MSC administration is a viable approach for ARDS resulting from influenza A(H7N9) infection, and could be potentially applicable to use in coronavirus-related respiratory infections.

These two studies, while suggestive, highlight a number of critical parameters that should be rigorously evaluated when assessing the potential use of MSCs in coronaviral and other viral respiratory infections. This include but are not limited to source of MSCs, dose, and dosing strategies (including the number and timing of administrations). It stands to reason that the optimal criteria for the selection of these metrics are determined by the target indication, not by cell availability or ease of cell isolation. Furthermore, these choices need to be backed by robust experimental data. An additional factor that was not clarified in either of these trials and that may be fundamental to the success of MSC-based cell therapies for any disease indication is the use of fresh versus cryopreserved and ready-toinject versus cell culture-conditioned cells [9] . These studies also highlight issues with the conduct of clinical trials for respiratory diseases, including those in critically ill patients.

Full information about inclusion and exclusion criteria, clinical course, comorbidities, coinfections, and laboratory tests, including investigative mechanistic evaluations, must be provided in a comprehensive manner. The latter should also include a robust description of statistical measures used to assess cohort sample sizes and to evaluate differences in outcome measures between treatment groups. While this level of rigor in reporting may be difficult to achieve under pandemic conditions, all authors and managing editors should aim to publish comprehensive results to inform future clinical trials and patient treatment options.

In addition to investigations ongoing in China and various academic institutions in Europe, North America, and elsewhere, several clinical-stage biopharmaceutical companies including Athersys, Mesoblast, and Pluristem are planning clinical trials to test their respective MSC-like products for treating COVID-19-associated ARDS. These trials span the gamut from compassionate use/hospital exemption to Phase III studies, and the respective platforms employ MSCs from different sources, such as bone marrow (Athersys and Mesoblast) and placenta (Pluristem), and also employ different routes of delivery including intravenous (Athersys, Mesoblast) and extravascular (Pluristem). Industries may be well positioned to conduct large, informative clinical trials in a timely fashion and acquire the necessary data to obtain market approval for their respective platforms by national regulatory bodies. However, these trials must also be conducted under appropriate trial design, regulatory oversight, and transparency of reporting results. The companies listed above have all announced ongoing conversations with national regulators to launch trials and begin treatment of the first subjects in a short time span. [10] [11] [12] 

As governmental organizations, health care providers, and clinical investigators around the world attempt to navigate these unprecedented times, they need to lead by identifying and selecting only the most pertinent evidence for clinical testing and authorization. These pressing actions still need to occur under appropriate ethical and scientific guidelines and undergo an appropriate, scientifically rigorous approval process overseen by duly empowered agencies. The ethical guidelines provided by the World Health Organization (WHO) are worthy baselines applicable to the many cell-based clinical trials that are being planned as a response to the COVID-19 public health emergency. [13] A highlight of this moral compass includes the registration of all clinical trials just as would be required in non-outbreak situations. It is also essential that the expected risks be reasonable in relation to anticipated benefits. In addition, other factors can challenge the trial's sponsors to obtain informed consent, as prospective participants might be in intensive care. One suggested solution is the appointment of proxy decision-makers that can sign consent on their behalf. This is an ethical issue that is approached differently in different countries. The U.S. Food and Drug Administration (FDA) has issued guidance to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic [14] . These guidelines are intended for ongoing trials that are not related to the treatment of COVID-19 patients. However, many of the assessments can also be applicable to planned COVID-19 trials. New logistics are proposed to cope with enforced confinement; notably, as trial participants may not be able to come to the investigational site for specified visits, sponsors are allowed to evaluate whether alternative methods can be implemented for remote safety assessments. Also, changes to the protocol to minimize or eliminate immediate hazards may be implemented without IRB approval, but must stille be reported afterwards. More directly, the FDA has created a special emergency program for possible therapies, the Coronavirus Treatment Acceleration Program (CTAP) [15] . The program is meant to fast-track new treatments to patients, provide immediate triage, and ensure response within a day of request receipt. Interactions are prioritized on the basis of each product's stage of development, with protocol review of prioritized products within 24 hours of submission and expedited quality assessments for products to treat COVID-19 patients and to transfer manufacturing to alternative or new sites to avoid supply disruption. Other decisions include the redeployement of medical, operations, policy, and regulatory staff to review teams dedicated to COVID-19 therapies, as well as involvement of senior management in review of submissions. Most importantly, it provides resources to healthcare providers and researchers to help them submit emergency requests to use investigational products for patients with COVID-19. All of these are applicable to cell-based therapy investigations.

MSCs have been administered to large numbers of patients in various clinical contexts without evidence of significant safety-related issues [16] but less data is available for critically ill patients. Importantly, data from a Phase2a trial in ARDS due to other etiologies reported no significant infusional toxicities or other safety issues other than the death of one patient 24h after MSC infusion, which was judged to be unrelated to cell administration. [6] With respect to clinical efficacy results to date are ambiguous. For example, the Phase2a ARDS START trial reported a trend toward higher mortality in the MSC vs. placebo arm that was attributed to patient randomization, [6] and results from a Phase1/2 trial of MSC administration in ARDS sponsored by Athersys is awaiting publication. One significant unresolved issue in this respect is which COVID-19 patient population to target. Critically ill patients with ARDS requiring supportive measures, including intubation and mechanical ventilation, are a logical population. Arguments can also be made for severely infected patients with currently recognized risk factors, such as advanced age, cardiovascular disease, or hematologic malignancies requiring immunotherapy or chemotherapy. Whether patients with moderate or mild disease should be enrolled in clinical investigations remains less clear. [3] Another significant issue is the evolving understanding of the pathogenesis of ARDS in COVID-19 patients, how this may differ from other etiologies, and the corresponding effects on potential cell-based therapies.

It is also imperative that clinical investigations be conducted in a transparent manner, according to established precedents for clinical research of new therapies in critical illness [17] . We also advocate rapid and full data sharing, believing that every researcher who engages in generation of information related to a public health emergency or acute public health event with the potential to progress to an emergency has a fundamental moral obligation to share preliminary results once they are adequately quality controlled for release. Given the rapid spread of COVID-19 and the increasing numbers of cell-based therapy investigations, a coordinating center to expedite congruent trial design and appropriate data dissemination would be of significant benefit.

We must also take a strong stance against the rogue stem-cell clinic industry which has already begun to offer unproven therapies for COVID19. The International Society for Cellular and Gene Therapies (ISCT) [18] , International Society for Stem Cell Research (ISSCR) [19] , Alliance for Regenerative Medicine (ARM) [20] , and other organizations have aligned their stances against this predatory behavior, but more regulatory oversight and action are needed. Only then can a rationale evidence-based platform for potential thereapeutic use of cell-based therapies be developed

Maroun Khoury is the CSO of Cells for Cells, all other authors have declared that no competing interest exists.

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Transplantation of ACE2 -Mesenchymal Stem Cells Improves the Outcome of Patients

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