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

Abstract

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.

Short-term assays for mesenchymal stromal cell immunosuppression of T-lymphocytes

“…Therapies focused on preventing secondary damage post injury and suppressing a dysregulated immune response will serve to improve patient outcomes. Although treating coagulopathic patients with pro-coagulant MSCs must be approached with caution ( 16 , 19 , 20 , 103 ), MSCs’ immunomodulation potential suggests that their use in any population such as trauma patients who are susceptible to a hyperactive immune response and coagulopathy ( 110 ) may be beneficial. It is hoped that these short-term assays will aid in developing, screening, and customizing cell therapy for the aid of the patient.…”

“…Their potential was also recently realized in several COVID therapies (12)(13)(14)(15). The most comprehensive and up-to-date summary on the use of MSCs for COVID19 was recently published by Couto et al in Frontiers Immunology 2023 (16).…”

“…The most comprehensive and up-to-date summary on the use of MSCs for COVID19 was recently published by Couto et al. in Frontiers Immunology 2023 ( 16 ).…”

Umbilical cord blood and cord tissue banking as somatic stem cell resources to support medical cell modalities

“…In addition to the clinical trials using UC-MSCs introduced in Tables 1 and 2 , there are accumulating early-phase clinical trials using UC-MSCs [ 17 , 20 , 23 , 33 – 35 ] for engraftment facilitation in HSCT for aplastic anemia [ 36 ], neurogenic injuries, diabetes mellitus (DM), heart and angioplasty, liver damage including liver cirrhosis, inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, prevention of acute rejection in renal transplantation, and collagen diseases [ 33 ]. The number of relevant clinical trials on the NIH clinical trial website ( https://00m.in/HHVJP ) has increased up to 95 trials, including complete, recruiting, and not-yet-recruiting status, as of the end of May 2023.…”

Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling

“…After establishing the functional role of RABs directed against the angiotensin II type 1 receptor (AT1R) and endothelin receptor type A (ETAR) for vascular integrity and graft function/survival in the KTx setting ( 4 , 8 , 9 , 11 – 16 ), subsequent studies have identified several RABs directed against GPCR targets typically associated with the vasculature, such as protease-activated receptors (PARs), neuronal and chemokine receptors, and the levels of these RABs are often modulated with patient age and disease status ( 1 , 17 , 18 ). Vasculature-associated RAB targets can be found on different types of micro-/macro-vascular endothelial cells (ECs), vascular smooth muscle cells (VSCMs), and perivascular multipotent mesenchymal stromal/stem cells (MSCs), but also neuronal cells, which are all often employed as model systems to study respective molecular signaling mechanisms ( 1 , 19 , 20 ).…”