Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery

During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection

Cell Therapy Trends

<p>This set provides some statistical data in the field of cell therapy. Input measured as number of clinical trials. Output measured as results of clinical trials and studies, published in medical literature. </p

Allogeneic versus autologous commercial/ industry-sponsored cell therapy clinical studies, listed as trials in international databases

<p>This graph demonstrates the trend in industry-sponsored cell therapy clinical trials, listed in international databases and involved autologous versus allogeneic donor cell types.</p> <p><strong>Methodology</strong> described here:</p> <p>http://celltrials.info/2015/01/22/2014-report/</p> <p>Legend:</p> <p>X axis: years, since 2011</p> <p>Y axis: Number of "trials" newly listed in international registeries. It is not cumulative number - only listings, appeared between January 1 of particular year and January 1 of the next year.</p> <p>Columns demonstrate relation of autologous versus allogeneic donor cell types, explored in clinical studies.</p> <p>"Industry" is a generic term, used to describe all "commercial" studies, listed in databases as (1) sponsored by a company or (2) private clinic or (3) involved company as collaborator, which manufactured/ prepared therapeutic cellular product. </p

Number of academic versus industry-sponsored cell therapy trials, listed in databases

<p>This graph demonstrates the trend in cell therapy clinical trials, listed in international databases.</p> <p><strong>Methodology</strong> described here:</p> <p>http://celltrials.info/2015/01/22/2014-report/</p> <p><strong>Legend</strong>:</p> <p>X axis: years, since 2011</p> <p>Y axis: Number of "trials" <strong>newly</strong> listed in international registeries. It is not cumulative number - only listings, appeared between January 1 of particular year and January 1 of the next year.</p> <p><strong>Definitions</strong>:</p> <p>"Industry" is a generic term, used to describe all "commercial" studies, listed in databases as (1) sponsored by a company or (2) private clinic or (3) involved company as collaborator, which manufactured/ prepared therapeutic cellular product.</p> <p>"Academia" is a generic term, used to describe all other types of sponsorship, different from "industry"/ commercial.</p> <p> </p> <p> </p

Trend in number of clinical studies, involved mesenchymal stromal cells (MSC), listed as trials in international registries

<p>This graph demonstrates the trend in sponsorship of cell therapy clinical trials, involved mesenchymal stromal cells (MSC) listed in international databases.</p> <p><strong>Methodology</strong> described here:</p> <p>http://celltrials.info/2015/01/22/2014-report/</p> <p><strong>Legend</strong>:</p> <p>X axis: years, since 2011</p> <p>Y axis: Number of "trials" newly listed in international registeries. It is not cumulative number - only listings, appeared between January 1 of particular year and January 1 of the next year.</p

Phases of CAR cell therapy trials registered worldwide

<div><b>Methodology:</b></div>10 International public databases (including NCT, EudraCT, UMIN, ChiTCR, ANZCTR...) were screened to identify CAR clinical trials, registered in any period of time until December 31 of 2016. At least 10 combinations of key words were used in search queries (including "cell", "CAR cell", "chimeric antigen", "T cell", "T cell gene modified"...). Only CAR genetic modification of cells was included. At least 23 parameters were captured manually, if information was available. Validity of captured data was verified by second researcher (CellTrials.org). Overlaps between databases were excluded from analysis. Statistical information was analyzed in MS Exel

Total number of CAR cell therapy trials listed in databases

<b>Methodology:</b><br>10 International public databases (including NCT, EudraCT, UMIN, ChiTCR, ANZCTR...) were screened to identify CAR clinical trials, registered in any period of time until December 31 of 2016. At least 10 combinations of key words were used in search queries (including "cell", "CAR cell", "chimeric antigen", "T cell", "T cell gene modified"...). Only CAR genetic modification of cells was included. At least 23 parameters were captured manually, if information was available. Validity of captured data was verified by second researcher (CellTrials.org). Overlaps between databases were excluded from analysis. Statistical information was analyzed in MS Exel. <br

Trend in clinical trials using fresh SVF vs. culture expanded adipose-derived cells

<p>This graph compares a number of clinical studies, involved  involved adipose tissue-derived Stromal Vascular Fraction (SVF) and stem cells expanded in culture.  Clinical studies, listed in international databases as trials.</p> <p><strong>Methodology</strong> described here:</p> <p>http://celltrials.info/2015/01/22/2014-report/</p> <p><strong>Legend</strong>:</p> <p>X axis: years, since 2011</p> <p>Y axis: Relative % and number of "trials" newly listed in international registeries. It is not cumulative number - only listings, appeared between January 1 of particular year and January 1 of the next year.</p> <p><strong>Definitions</strong>:</p> <p>Adipose tissue-derived cells include (1) freshly isolated SVF, used therapeutically at point-of-care and (2) cultured and ex-vivo expanded stem cells.</p