Cell therapy for patients with severe spinal cord injury (phase I/IIа): Assessment of safety and primary efficacy of therapy

Background. The problem of pathogenetic treatment of spinal cord injury (SCI) is extremely acute, especially against the background of the growing number of SCI in modern conditions. The world literature widely presents the scientific research on the development and application of regenerative technologies and cell therapy effective for patients with SCI. One of the most promising areas is the use of stem cells. The human umbilical cord blood cells (HUCBCs) is one of the sources for obtaining stem cells having a number of serious advantages such as high efficiency in the patients’ treatment with traumatic lesions of the central nervous system.

Aim. To evaluate the safety and primary efficacy of serial systemic (intravenous) administration of allogeneic mononuclear cells of the HUPBC to adult patients with gross neurological deficit because of acute period of severe contusion SCI.

Material and methods. Phase I of the SUBSCI I / IIa study included 10 patients (experimental and control groups) with severe SCI (cervical / thoracic / upper lumbar) in the acute period with gross neurological deficit (A / B on the ASIA scale). The conducted treatment included 4 systemic (intravenous) administrations of HUCBCs (allogeneic and compatible by AB0 and Rh factor) within 3 days from the moment of SCI, strictly after the primary surgical intervention. Observation period lasted 12 months after trauma. Safety assessment included the registration of all adverse events (AE) during the observation period with their further classification by severity (CTCAE v. 5.0) and potential connection with the cell therapy. The primary efficacy assessment was the identification of the neurological deficit dynamics (ASIA) – assessment of the restoration degree of motor and sensory functions of the lower extremities during the 1st year.

Results and discussion. A total of 419 AEs were detected in 10 patients, but only 2 of them (clinically insignificant) were assessed as probably related to cell therapy, the remaining 417 were not related to therapy. All patients had no signs of immunization to the administered HUCBCs samples. The analysis of the neurological deficit dynamics indicates the reliable restoration of motor functions in patients after cell therapy, compared with the control group.

Conclusion. Based on the results obtained, the systemic administration of allogeneic HUPBC, selected without taking into account the HLA system, can be considered as a safe and effective method for treating contusion SCI in the acute period.

1. Krylov V.V., Grin A.A., Timerbaev V.Kh. et al. Vertebral trauma and spinal cord injury. Moscow: Print-Studio, 2014. 420 p. (In Russ.).

2. Smirnov V.А., Grin А.А., Krylov V.V. Regenerative treatment of spinal cord injury. Literature review. Part 1. Neyrokhirurgiya = Russian Journal of Neurosurgery 2019;21(2):66–75. (In Russ.). DOI: 10.17650/1683-3295-2019-21-2-66-75

3. Pickett G.E., Campos-Denitez M., Keller J.L., Duggal N. Epidemiology of traumatic spinal cord injury in USA and Canada. Spine (Phila Pa 1976) 2006;31(7):799–805. DOI: 10.1097/01.brs.0000207258.80129.03

4. van den Berg M.E., Castellote J.M., Mahillo-Fernandez I., de Pedro-Cuesta J. Incidence of spinal cord injury worldwide: A systematic review. Neuroepidemiology 2010;34(3):184–92. DOI: 10.1159/000279335

5. Lee B.A., Leiby B.E., Marino R.J. Neurological and functional recovery after thoracic spinal cord injury. J Spinal Cord Med 2016;39(1):67–76. DOI: 10.1179/2045772314Y.0000000280

6. Hawryluk G.W., Rowland J., Kwon B.K., Fehlings M.G. Protection and repair of the injured spinal cord: a review of completed, ongoing, and planned clinical trials for acute spinal cord injury. Neurosurg Focus 2008;25(5):e1–14. DOI: 10.3171/FOC.2008.25.11.E14

7. Vaccaro A.R., Daugherty R.J., Sheehan T.P. et al. Neurologic outcome of early versus late surgery for cervical spinal cord injury. Spine (Phila Pa 1976) 1997;22(22):2609–13. DOI: 10.1097/00007632-199711150-00006

8. Schwab M.E., Brösamle C. Regeneration of lesioned corticospinal tract fibers in the adult rat spinal cord under experimental conditions. Spinal Cord 1997;35(7):469–73. DOI: 10.1038/sj.sc.3100457

9. Fehlings M.G., Vaccaro A., Wilson J.R. et al. Early versus delayed decompression for traumatic cervical spinal cord injury: results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS). PLoS One 2012;7(2):e32037. DOI: 10.1371/journal.pone.0032037

10. Domingo A., Al-Yahya A.A., Asiri Y. et al. A systematic review of the effects of pharmacological agents on walking function in people with spinal cord injury. J Neurotrauma 2012;29(5):865–79. DOI: 10.1089/neu.2011.2052

11. Evaniew N., Belley-Côté E.P., Fallah N. et al. Methylprednisolone for the treatment of patients with acute spinal cord injuries: A systematic review and meta-analysis. J Neurotrauma 2016;33(5):468–81. DOI: 10.1089/neu.2015.4192

12. Fehlings M.G., Theodore N., Harrop J. et al. A phase I/IIa clinical trial of a recombinant rho protein antagonist in acute spinal cord injury. J Neurotrauma 2011;28(5):787–96. DOI: 10.1089/neu.2011.1765

13. Nakamura M., Nagoshi N., Fujiyoshi K. et al. Regenerative medicine for spinal cord injury: Current status and open issues. Inflamm Regen 2009;29(3):198–203. DOI: 10.2492/inflammregen.29.198

14. Li J., Lepski G. Cell transplantation for spinal cord injury: A systematic review. Biomed Res Int 2013;786475. DOI: 10.1155/2013/786475

15. Willerth S.M., Sakiyama-Elbert S.E. Cell therapy for spinal cord regeneration. Adv Drug Deliv Rev 2008;60(2):263–76. DOI: 10.1016/j.addr.2007.08.028

16. Harris D.T. Non-haematological uses of cord blood stem cells. Br J Haematol 2009;147(2):177–84. DOI: 10.1111/j.1365-2141.2009.07767.x

17. Henon P.R. Human embryonic or adult stem cells: An overview on ethics and perspectives for tissue engineering. Adv Exp Med Biol 2003;534:27–45. DOI: 10.1007/978-1-4615-0063-6_3

18. Ryabov S.I., Smirnov V.A., Green A.A. et al. Human umbilical cord blood cell administration reduces behavioral deficit after severe spinal cord injury. In: 5th International Congress Biotechnologies for Spinal Surgery (BIOSPINE 2015). Eur Spine J 2015;24(3): 657–58. DOI: 10.1007/s00586-015-3794-4

19. Ryabov S.I., Zvyagintseva M.A., Pavlovich E.P. et al. Efficiency of transplantation of human placental/umbilical blood cells to rats with severe spinal cord injury. Bull Exp Biol Med 2014;157(1):85–8. DOI: 10.1007/s10517-014-2498-9

20. Vladimir A. Smirnov; Sklifosovsky Institute of Emergency Care. Allogeneic Mononuclear umbilical cord blood systemic infusions for adult patients with severe acute contusion spinal cord injury: Phase I safety study and phase IIa primary efficiency study. Clinical Trials identifier, NCT 04331405, 2020. Available at: https://clinicaltrials.gov/study/NCT04331405

21. International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). Available from: http://www.asiaspinalinjury.org/elearning/ISNCSCI.php

22. Laskowitz D.T., Bennett E.R., Durham R.J. et al. Allogeneic umbilical cord blood infusions for adults with ischemic stroke: Clinical outcomes from a phase 1 safety study. Stem Cells Transl Med 2018;7(7):521–9. DOI: 10.1002/sctm.18-0008

23. Sun T., Ma Q.H. Repairing neural injuries using human umbilical cord blood. Mol Neurobiol 2013;47(3):938–45. DOI: 10.1007/s12035-012-8388-0

24. Kuh S., Cho Y., Yoon D. et al. Functional recovery after human umbilical cord blood cells transplantation with brain-derived neutrophic factor into the spinal cord injured rat. Acta Neurochir (Wien) 2005;147(9):985–92. DOI: 10.1007/s00701-005-0538-y

25. Muheremu A., Peng J., Ao Q. Stem cell based therapies for spinal cord injury. Tissue Cell 2016;48(4):328–33. DOI: 10.1016/j.tice.2016.05.008