Assessment of the ongoing cell-based clinical trials registered during the COVID-19 outbreak
At the time of this review, the number of cell-based clinical investigations to explore the therapeutic potential of cell treatment for SARS-CoV-2 infected patients registered since late January 2020 on the US National Institutes of Health (NIH) ClinicalTrials.gov database and the Chinese Clinical Trial Registry (www.chictr.org.cn), also accessible from the World Health Organization International Clinical Trial Registry Platform (WHO-ICTRP), has reached 27 entries with a total of approximately 1287 patients considered for enrolment (table 2). There are three main interventions: MSCs (n=17; 781 patients), MSC derivatives (conditioned media or extracellular vesicles; n=4; 176 patients), or other cell sources (n=6; 330 patients). General common features of the investigations include: 1) systemic administration, jointly with or followed by the recommended conventional supportive treatments for severe or critical SARS-CoV-2 infection [49]; 2) age range 18–80 years with no sex restrictions; 3) follow-up for at least 3 months; and 4) clinical samples collected will be throat secretions and/or blood. For the MSC investigations, 10 out of 17 will utilise UC-MSCs, one out of 17 will utilise menstrual blood-origin MSCs, and six out of 17 do not disclose the MSC tissue source. Notably, no apparent MSCs of bone marrow origin are being utilised, despite the majority of pre-clinical investigations for non-viral-induced acute lung injuries having utilised BM-MSCs. There is little clarification of use of cryopreserved versus continuously cultured cells [5]. Only six out of 16 disclose the intended cell injection dose, among which only four are correlated with the patient body weight. The intravenous dosing range varies between 0.4 and 42×106 cells·kg−1. In comparison, the highest dose of MSCs used in the published literature for clinical trials in non-viral ARDS was 10×106 cells·kg−1 (START trial) [50]. The dosing strategy ranges between a single dose and five doses, with an average frequency of every 2 days.
TABLE 2 Cell-based clinical trials using MSCs, MSC derivatives and other cells
Registration date and execution date range DD-MM-YYYY Study phase and recruitment status ID and URL Title Cell type Total participants n Intervention or treatment
Clinical trials based on MSCs
1 14-02-2020; 20-02-2020 to 20-02-2021 0Not recruiting ChiCTR2000029816;http://www.chictr.org.cn/showproj.aspx?proj=49389 Clinical study for cord blood mesenchymal stem cells in the treatment of acute novel coronavirus pneumonia (COVID-19) UCB-MSCs; UCB-NK cells 60 Experimental groups: conventional treatment followed by i.v. infusion of 1) UCB-MSCs and 2) UCB-MSCs combined with UCB-NK cellsControl group: conventional treatment
2 14-02-2020; 20-02-2020 to 20-02-2021 0Not recruiting ChiCTR2000029817;http://www.chictr.org.cn/showproj.aspx?proj=49384 Clinical study of cord blood NK cells combined with cord blood mesenchymal stem cells in the treatment of acute novel coronavirus pneumonia (COVID-19) NK cells and UCB-MSCs 60 Experimental (high-dose) group: high-dose NK cells (>5×109) and MSCs (>5×109), i.v. infusion once every 2 days for a total of 5 timesConventional dose group: conventional dose NK cells (>3×109) and MSCs (>3×109), i.v. infusion once every 2 days for a total of 3 timesPreventive dose group: preventive dose NK cells (>3×109) and MSCs (>3×109), i.v. infusion once every week for a total of 1 time
3 07-02-2020; 15-01-2020 to 31-12-2022 0Recruiting ChiCTR2000029606;http://www.chictr.org.cn/showproj.aspx?proj=49146 Clinical study for human menstrual blood-derived stem cells in the treatment of acute novel coronavirus pneumonia (COVID-19) MenSCs 63 Experimental group A:Conventional treatment followed by i.v.  infusion of MenSCsControl group A: conventional treatmentExperimental group B:1: Artificial liver therapy + conventional treatment2: Artificial liver therapy followed by i.v. infusion of MenSCs + conventional treatmentControl group B: conventional treatment
4 07-02-2020; 06-02-2020 to 30-09-2020 2Recruiting NCT04269525;https://clinicaltrials.gov/show/NCT04269525 Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) treatment for the 2019-novel coronavirus (nCOV) pneumonia UC-MSCs 10 Experimental group: UC-MSCs 3.3×107 cells per 50 mL per bag, 3 bags each time; UC-MSCs will be infused i.v. on the 1st, 3rd, 5th and 7th days after enrolment, once each dayControl group: none specified
5 05-02-2020; 31-01-2020 to 31-12-2020 0Recruiting ChiCTR2000029580;http://www.chictr.org.cn/showproj.aspx?proj=49088 A prospective, single-blind, randomized controlled trial for ruxolitinib combined with mesenchymal stem cell infusion in the treatment of patients with severe 2019-nCoV pneumonia (novel coronavirus pneumonia, NCP) MSCs 70 Experimental group: ruxolitinib combined with MSCsControl group: routine treatment
6 27-01-2020; 21-01-2020 to 31-12-2021 1Recruiting NCT04252118;https://clinicaltrials.gov/show/NCT04252118 Mesenchymal stem cell treatment for pneumonia patients infected with 2019 novel coronavirus MSCs 20 Experimental group: 3.0×107 MSCs i.v. at days 0, 3 and 6Control group: none specified
7 14-02-2020; 16-02-2020 to 15-02-2022 NANot recruiting NCT04273646;https://clinicaltrials.gov/ct2/show/NCT04273646 Study of human umbilical cord mesenchymal stem cells in the treatment of novel coronavirus severe pneumonia UC-MSCs 48 Experimental group: 4 times of UC-MSCs, 0.5×106 UC-MSCs·kg−1 body weight i.v. at days 1, 3, 5 and 7Control group: none specified
8 28-02-2020; 19-02-2020 to 20-02-2021 1Recruiting ChiCTR2000030300;http://www.chictr.org.cn/showprojen.aspx?proj=50022 Umbilical cord mesenchymal stem cells (hucMSCs) in the treatment of high risk novel coronavirus pneumonia (COVID-19) patients UC-MSCs 9 Experimental group: MSCsControl group: none specified
9 26-02-2020; 14-02-2020 to 31-05-2020 NANot recruiting ChiCTR2000030224;http://www.chictr.org.cn/showprojen.aspx?proj=49968 Clinical study of mesenchymal stem cells in treating severe novel coronavirus pneumonia (COVID-19) MSCs 32 Experimental group 1: critical group, intervention, injecting MSCsExperimental group 2: severe group, intervention, injecting MSCsControl group 3: control of the critical group, intervention, injecting normal salineControl group 4: control of the severe group, intervention, injecting normal saline
10 24-02-2020; 17-02-2020 to 17-04-2020 0Not recruiting ChiCTR2000030173;http://www.chictr.org.cn/showprojen.aspx?proj=49229 Key techniques of umbilical cord mesenchymal stem cells for the treatment of novel coronavirus pneumonia (COVID-19) and clinical application demonstration UC- MSCs 60 Experimental group: UC-MSCsControl group: Conventional treatment
11 24-02-2020; 24-02-2020 to 31-05-2020 2Not recruiting ChiCTR2000030138;http://www.chictr.org.cn/showproj.aspx?proj=50004 Clinical trial for human mesenchymal stem cells in the treatment of severe novel coronavirus pneumonia (COVID-19) UC-MSCs 60 Experimental group: i.v. injection of UC-MSCsControl group: routine treatment + placebo
12 23-02-2020; 01-02-2020 to 31-08-2020 NARecruiting ChiCTR2000030116;http://www.chictr.org.cn/showproj.aspx?proj=49901 Safety and effectiveness of human umbilical cord mesenchymal stem cells in the treatment of acute respiratory distress syndrome of severe novel coronavirus pneumonia (COVID-19) UC-MSCs 16 Experimental group: different stem cell dosesControl group: none specified
13 22-02-2020; 01-03-2020 to 31-12-2021 0Not recruiting ChiCTR2000030088;http://www.chictr.org.cn/showproj.aspx?proj=49902 Umbilical cord Wharton's jelly derived mesenchymal stem cells in the treatment of severe novel coronavirus pneumonia (COVID-19) UC-Wharton's jelly MSCs 40 Experimental group: i.v. injection of Wharton's jelly MSCs (1×106 MSCs·kg−1), cell suspension volume 40 mLControl group: i.v. 40 mL saline
14 20-02-2020; 06-02-2020 to 05-02-2022 NARecruiting ChiCTR2000030020;http://www.chictr.org.cn/showproj.aspx?proj=49812 The clinical application and basic research related to mesenchymal stem cells to treat novel coronavirus pneumonia (COVID-19) MSCs 20 Experimental group: case series, MSC therapyControl group: none specified
15 18-02-2020; 30-01-2020 to 31-03-2020 1–2Recruiting ChiCTR2000029990;http://www.chictr.org.cn/showproj.aspx?proj=49674 Clinical trials of mesenchymal stem cells for the treatment of pneumonitis caused by novel coronavirus pneumonia (COVID-19) MSCs 120 Experimental group: MSCsControl group: saline
16 28-02-2020; 28-02-2020 to 31-12-2021 1–2Not recruiting NCT04288102;https://clinicaltrials.gov/ct2/show/NCT04288102 Treatment with mesenchymal stem cells for severe corona virus disease 2019 (COVID-19) MSCs 45 Experimental group: 3 times of MSCs; if body weight ≥70 kg, 4.0×107 cells each time; if body weight <70 kg, 3.0×107 cells each time; i.v. at days 0, 3 and 6Control group: saline containing 1% human serum albumin (solution used for MSCs), 3 times of placebo, i.v. at days 0, 3 and 6
17 24-02-2020; 24-02-2020 to 01-02-2021 NARecruiting NCT04293692;https://clinicaltrials.gov/show/NCT04293692 Therapy for pneumonia patients infected by 2019 novel coronavirus UC-MSCs 48 Experimental group: conventional treatment plus 4 times of 0.5×106 UC-MSCs·kg−1 body weight suspended in 100 mL saline containing 1% human albumin, i.v. at days 1, 3, 5 and 7Control group: conventional treatment plus 4 times of placebo (100 mL saline containing 1% human albumin), i.v. at days 1, 3, 5 and 7
Clinical trials based on MSC derivatives
1 04-02-2020; 05-02-2020 to 30-04-2021 0Not recruiting ChiCTR2000029569;http://www.chictr.org.cn/showproj.aspx?proj=49062 Safety and efficacy of umbilical cord blood mononuclear cells conditioned medium in the treatment of severe and critically novel coronavirus pneumonia (COVID-19): a randomized controlled trial UC-MSCs CM 30 Experimental group: conventional treatment combined with UC-MSCs CMControl group: conventional treatment
2 19-02-2020; 15-02-2020 to 31-07-2020 1Not recruiting NCT04276987;https://clinicaltrials.gov/ct2/show/NCT04276987 A pilot clinical study on inhalation of mesenchymal stem cells exosomes treating severe novel coronavirus pneumonia AT-MSC exosomes 30 Experimental group: 5 times aerosol inhalation of MSC-derived exosomes, 2.0×108 nano vesicles per 3 mL at days 1, 2, 3, 4 and 5Control group: none specified
3 26-02-2020; 28-02-2020 to 31-05-2020 0Not recruiting ChiCTR2000030261;http://www.chictr.org.cn/showprojen.aspx?proj=49963 A study for the key technology of mesenchymal stem cells exosomes atomization in the treatment of novel coronavirus pneumonia (COVID-19) MSC exosomes 26 Experimental group: aerosol inhalation of exosomesControl group: blank
4 03-03-2020; 31-01-2020 to 31-01-2021 NANot recruiting ChiCTR2000030484;http://www.chictr.org.cn/showproj.aspx?proj=50263 UC-MSCs and exosomes treating patients with lung injury following novel coronavirus pneumonia (COVID-19) UC-MSCs and exosomes 90 Experimental groups:Group 1: UC-MSCs i.v. 5×107 cells each time, once a week, twice per courseGroup 2: UC-MSCs i.v. 5×107 cells each time, once a week, twice per course, a total of 2 courses; exosomes i.v. administration, 180 mg each time, once a day, 7 days per course, 2 courses in totalControl group: same amount of placebo (stem cell solvent)
Clinical trials based on other cell types
1 14-02-2020; 20-02-2020 to 20-02-2021 0Not recruiting ChiCTR2000029812;http://www.chictr.org.cn/showproj.aspx?proj=49374 Clinical study for umbilical cord blood mononuclear cells in the treatment of acute novel coronavirus pneumonia (COVID-19) UCBMCs 60 Experimental group: conventional treatment followed by i.v. UCBMC preparationsControl group: conventional treatment
2 05-02-2020; 05-02-2020 to 30-04-2021 0Recruiting ChiCTR2000029572;http://www.chictr.org.cn/showproj.aspx?proj=41760 Safety and efficacy of umbilical cord blood mononuclear cells in the treatment of severe and critically novel coronavirus pneumonia (COVID-19): a randomized controlled clinical trial UCBMCs 30 Experimental group: conventional treatment combined with UCBMCsControl group: conventional treatment
3 17-02-2020; 24-02-2020 to 31-12-2024 1–2Recruiting NCT04276896;https://clinicaltrials.gov/show/NCT04276896 Function and safety study of SARS-CoV-2 synthetic minigene vaccines Autologous LV-DC vaccine or antigen-specific cytotoxic T-cells 100 Experimental group: 5×106 LV-DC vaccine or 1×108 cytotoxic T-cells as a single infusion via subcutaneous fluids or i.v. injection; may receive additional infusionsControl group: none specified
4 13-02-2020; 20-02-2020 to 30-12-2020 1Recruiting NCT04280224;https://clinicaltrials.gov/show/NCT04280224 NK cells treatment for novel coronavirus pneumonia NK cells 30 Experimental group: conventional treatment plus twice a week of NK cells (0.1–2×107 NK cells·kg−1 body weight)Control group: conventional treatment
5 06-03-2020; 10-04-2020 to 10-11-2020 2Not recruiting NCT04299152;https://clinicaltrials.gov/ct2/show/NCT04299152 Clinical application of stem cell educator therapy for the treatment of viral inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) CB-SCs 20 Experimental group: combination product: stem cell educator-treated mononuclear cells apheresis therapy circulates a patient's blood through a blood cell separator, briefly cocultures the patient's immune cells with adherent CB-SCs in vitro, and returns the “educated” autologous immune cells to the patient's circulationControl group: conventional treatment: regular treatments, only addressing their symptoms, such as reducing fever and cough
6 28-02-2020; 01-03-2020 to 17-02-2021 0Not recruiting ChiCTR2000030088;http://www.chictr.org.cn/showproj.aspx?proj=49779 Clinical trial for umbilical cord blood CIK and NK cells in the treatment of mild and general patients infected with novel coronavirus pneumonia (COVID-19) CIK and NK cells 90 Experimental groups:CIK group: UCB CIK cells (1.6×108 cells·kg−1) injected twice every other dayNK group: UCB NK cells (1.6×108 cells·kg−1) injected twice every other dayControl group: conventional therapy
MSCs: mesenchymal stem (stromal) cells; i.v.: intravenous; UCB: umbilical cord blood; NK: natural killer; MenSCs: mesenchymal stem cells derived from menstrual fluid; UC: umbilical cord; CM: conditioned medium; AT: adipose tissue; UCBMCs: umbilical cord blood-derived mononuclear cells; LV-DC: lentivirus dendritic cell; CB-SCs: cord blood stem cells; CIK: cytokine-induced killer.Four of the trials will utilise either MSC-derived conditioned media or extracellular vesicles. Two of these propose aerosol inhalation of MSC-derived extracellular vesicles, one from AD-MSCs, for which there is no pre-clinical supporting data. Six investigations will utilise other cells, including umbilical cord blood-derived mononuclear cells, cytotoxic T-cells, dendritic cells, NK cells, cord blood stem cells and cytokine-induced killer cells, of which only the latter investigation describes dosing and frequency of injections. As best as we can ascertain, there are no apparent pre-clinical data to support the rationale for any of these approaches.