Transient Fever: The Sole Treatment-Related Adverse Event Associated with Mesenchymal Stromal Cells and Solid Clues from the Real World

Overview

Journal Curr Stem Cell Res Ther

Publisher Bentham Science Publishers

Specialties Cell Biology
Pharmacology

Date 2023 Nov 1

PMID 37909436

Authors

Yang Wang

Qiuying Mou

Hanxiao Yi

Zilu Meng

Affiliations

Soon will be listed here.

Abstract

Background: The number of trials investigating mesenchymal stromal cells (MSCs) soars within 3 years which urges a study analysing emerging MSC treatment-related adverse events.

Aim: To assess the safety of MSC therapy and provide solid evidence for clinical translation of MSC.

Methods: A meta-analysis of randomized clinical trials (RCTs) published up to April 20th, 2023 was performed. Odds ratio (OR) and 95% confidential intervals (CIs) were used to display pooled results.

Results: 152 randomized clinical trials (RCTs) that incorporated 9228 individuals treated with MSCs from autologous or allogenic adipose tissue, bone marrow, Wharton's Jelly, and placenta tissue were included in the analysis. We discovered appropriate 21 MSC treatment-related adverse events (TRAEs), of which fever [OR, 1.61, 95% CI: 1.22-2.11, p<0.01] was the sole event that was closely associated with MSC therapy. MSCs also trended to lower the incidence rate of tachycardia [OR, 0.83, 95% CI: 0.64-1.09, p=0.14] and fatigue [OR, 0.18, 95% CI: 0.61-1.07, p=0.18]. A separate analysis of studies with long-term follow-up (more than 1 year) demonstrated the close relationship between MSCs and fever [OR, 1.75, 95% CI: 1.26-2.24, p<0.01]. The rest TRAEs did not associate themselves with MSC therapy. Dose-response was also conducted for fever, linearity was discovered between MSCs from allogeneic tissue and Wharton's Jelly and fever.

Conclusion: To date, our results suggest that fever is the only AE closely associated with MSCs.

References

Brody M, Agronin M, Herskowitz B, Bookheimer S, Small G, Hitchinson B . Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease. Alzheimers Dement. 2022; 19(1):261-273. PMC: 10084163. DOI: 10.1002/alz.12651. View

Centeno C, Fausel Z, Stemper I, Azuike U, Dodson E . A Randomized Controlled Trial of the Treatment of Rotator Cuff Tears with Bone Marrow Concentrate and Platelet Products Compared to Exercise Therapy: A Midterm Analysis. Stem Cells Int. 2020; 2020:5962354. PMC: 7204132. DOI: 10.1155/2020/5962354. View

Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, Makarem J, Nasiri R, Salahshour F . Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II. Stem Cell Res Ther. 2022; 13(1):96. PMC: 8899458. DOI: 10.1186/s13287-022-02771-w. View

Albu S, Kumru H, Coll R, Vives J, Valles M, Benito-Penalva J . Clinical effects of intrathecal administration of expanded Wharton jelly mesenchymal stromal cells in patients with chronic complete spinal cord injury: a randomized controlled study. Cytotherapy. 2020; 23(2):146-156. DOI: 10.1016/j.jcyt.2020.08.008. View

Ramkisoensing A, Pijnappels D, Askar S, Passier R, Swildens J, Goumans M . Human embryonic and fetal mesenchymal stem cells differentiate toward three different cardiac lineages in contrast to their adult counterparts. PLoS One. 2011; 6(9):e24164. PMC: 3170333. DOI: 10.1371/journal.pone.0024164. View

Ward M, Abadeh A, Connelly K . Concise Review: Rational Use of Mesenchymal Stem Cells in the Treatment of Ischemic Heart Disease. Stem Cells Transl Med. 2018; 7(7):543-550. PMC: 6052612. DOI: 10.1002/sctm.17-0210. View

Mashayekhi M, Mirzadeh E, Chekini Z, Ahmadi F, Eftekhari-Yazdi P, Vesali S . Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human. J Ovarian Res. 2021; 14(1):5. PMC: 7786909. DOI: 10.1186/s13048-020-00743-3. View

Sharifzadeh N, Ghasemi A, Tavakol Afshari J, Moharari F, Soltanifar A, Talaei A . Intrathecal autologous bone marrow stem cell therapy in children with autism: A randomized controlled trial. Asia Pac Psychiatry. 2020; 13(2):e12445. DOI: 10.1111/appy.12445. View

Zu Y, Zhou J, Fu Y, Fang B, Liu X, Zhang Y . Feasibility of reduced-dose posttransplant cyclophosphamide and cotransplantation of peripheral blood stem cells and umbilical cord-derived mesenchymal stem cells for SAA. Sci Rep. 2021; 11(1):253. PMC: 7794355. DOI: 10.1038/s41598-020-80531-7. View

10.

Lublin F, Bowen J, Huddlestone J, Kremenchutzky M, Carpenter A, Corboy J . Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study. Mult Scler Relat Disord. 2015; 3(6):696-704. DOI: 10.1016/j.msard.2014.08.002. View

11.

Tsiapalis D, ODriscoll L . Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications. Cells. 2020; 9(4). PMC: 7226943. DOI: 10.3390/cells9040991. View

12.

Roth M, Spaniol K, Kordes C, Schwarz S, Mertsch S, Haussinger D . The Influence of Oxygen on the Proliferative Capacity and Differentiation Potential of Lacrimal Gland-Derived Mesenchymal Stem Cells. Invest Ophthalmol Vis Sci. 2015; 56(8):4741-52. DOI: 10.1167/iovs.14-15475. View

13.

Xu X, Jiang W, Chen L, Xu Z, Zhang Q, Zhu M . Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial. Clin Transl Med. 2021; 11(2):e297. PMC: 7839959. DOI: 10.1002/ctm2.297. View

14.

FRIEDENSTEIN A, Chailakhyan R, Latsinik N, Panasyuk A . Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974; 17(4):331-40. DOI: 10.1097/00007890-197404000-00001. View

15.

Rebelatto C, Senegaglia A, Franck C, Daga D, Shigunov P, Stimamiglio M . Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial. Stem Cell Res Ther. 2022; 13(1):122. PMC: 8935270. DOI: 10.1186/s13287-022-02796-1. View

16.

Zhang Y, Zhang J, Yi H, Zheng J, Cai J, Chen W . A novel MSC-based immune induction strategy for ABO-incompatible liver transplantation: a phase I/II randomized, open-label, controlled trial. Stem Cell Res Ther. 2021; 12(1):244. PMC: 8050996. DOI: 10.1186/s13287-021-02246-4. View

17.

Amirdelfan K, Bae H, McJunkin T, DePalma M, Kim K, Beckworth W . Allogeneic mesenchymal precursor cells treatment for chronic low back pain associated with degenerative disc disease: a prospective randomized, placebo-controlled 36-month study of safety and efficacy. Spine J. 2020; 21(2):212-230. DOI: 10.1016/j.spinee.2020.10.004. View

18.

Squassoni S, Sekiya E, Fiss E, Lapa M, Cayetano D, Nascimento F . Autologous Infusion of Bone Marrow and Mesenchymal Stromal Cells in Patients with Chronic Obstructive Pulmonary Disease: Phase I Randomized Clinical Trial. Int J Chron Obstruct Pulmon Dis. 2022; 16:3561-3574. PMC: 8733220. DOI: 10.2147/COPD.S332613. View

19.

Schacher F, Martins Pezzi da Silva A, da Rocha Silla L, Alvares-da-Silva M . Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial. Can J Gastroenterol Hepatol. 2021; 2021:3662776. PMC: 8357501. DOI: 10.1155/2021/3662776. View

20.

Shahror R, Wu C, Chiang Y, Chen K . Genetically Modified Mesenchymal Stem Cells: The Next Generation of Stem Cell-Based Therapy for TBI. Int J Mol Sci. 2020; 21(11). PMC: 7312789. DOI: 10.3390/ijms21114051. View