Cell-based medicinal products: a review of current research

INTRODUCTION. Cell therapies and tissue-engineered products are aimed at patients with severe conditions (genetic and neurodegenerative disorders, cancers, musculoskeletal injuries, burns, etc.) that lack alternative treatment options. Analysis of clinical efficacy data on cell-based medicinal products is important for understanding their translational potential in personalised medicine.

AIM. This study aimed to review key trends in cell therapy, analyse data on approved cell therapies and tissue-engineered products, and assess challenges and prospects for their use.

DISCUSSION. This article analyses data on the composition of cell therapies and tissue-engi­neered products, indications for their use, and the results of clinical studies. Cell-based medicinal products are derived from autologous or allogeneic mesenchymal and limbal stem cells, epithelial cells, chondrocytes, native or genetically engineered haematopoietic stem cells, geneti­cally engineered lymphocytes (CAR-T, CAR-NK), etc. Medicinal products based on cell technologies have been approved in many countries, including the USA (approximately 30), the European Union (approximately 20), Japan (18), South Korea (15), etc. As of today, two cell therapies have been granted marketing authorisation in the Russian Federation. The first is based on CAR-T cells (a gene therapy product), and the other is based on chondrocytes (a cell-based medicinal product); the latter has been developed in Russia. The main advantages of cell therapy products include higher efficacy and fewer adverse drug reactions in comparison with standard treatment modalities. The main challenges of cell therapy include the risks of immune reactions and mutagenesis associated with lentiviral vectors or CRISPR/Cas9 technology, as well as limited efficacy of CAR-T and CAR-NK cells due to immunosuppressive properties of tumour microenvironment.

CONCLUSION. In comparison with conventional treatment approaches, the use of cell therapies and tissue-engineered products can help effectively eliminate defects in various body tissues, avoid highly invasive surgical interventions, and reduce regeneration time. Thus, ensuring development of similar but at the same time more affordable Russian medicinal products can bring great benefits for the healthcare system of the Russian Federation.

1. El-Kadiry AE, Rafei M, Shammaa R. Cell therapy: types, regulation, and clinical benefits. Front Med (Lausanne). 2021;8:756029. https://doi.org/10.3389/fmed.2021.756029

2. Han F, Wang J, Ding L, Hu Y, Li W, Yuan Z, et al. Tissue engineering and regenerative medicine: achievements, future, and sustainability in Asia. Front Bioeng Biotechnol. 2020;8:83. https://doi.org/10.3389/fbioe

3. O’Brien FJ, Duffy GP. Form and function in regenerative medicine: introduction. J Anat. 2015;227(6):705–6. https://doi.org/10.1111/joa.12401

4. Shumega AR, Pavlov YI, Chirinskaite AV, Rubel AA, Inge-Vechtomov SG, Stepchenkova EI. CRISPR/Cas9 as a mutagenic factor. Int J Mol Sci. 2024;25(2):823. https://doi.org/10.3390/ijms25020823

5. Grinev VV, Posrednik DV, Severin IN, Potapnev MP. Genetic modification of human cells using lentiviral transduction in vitro and ex vivo. Minsk: BSU; 2010 (In Russ.).

6. Wang Y, Yi H, Song Y. The safety of MSC therapy over the past 15 years: a meta-analysis. Stem Cell Res Ther. 2021;12(1):545. https://doi.org/10.1186/s13287-021-02609-x

7. Li C, Zhao H, Cheng L, Wang B. Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice. Cell Biosci. 2021;11(1):187. https://doi.org/10.1186/s13578-021-00698-y

8. Conwit RA. Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted? J Neurol Sci. 2006;251(1–2):1–2. https://doi.org/10.1016/j.jns.2006.07.009

9. Al-Chalabi A, Leigh PN. Recent advances in amyotrophic lateral sclerosis. Curr Opin Neurol. 2000;13(4):397–405. https://doi.org/10.1097/00019052-200008000-00006

10. Oh KW, Noh MY, Kwon MS, Kim HY, Oh SI, Park J, et al. Repeated intrathecal mesenchymal stem cells for amyotrophic lateral sclerosis. Ann Neurol. 2018;84(3):361–73. https://doi.org/10.1002/ana.25302

11. Honmou O, Yamashita T, Morita T, Oshigiri T, Hirota R, Iyama S, et al. Intravenous infusion of auto serum-­expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series. Clin Neurol Neurosurg. 2021;203:106565. https://doi.org/10.1016/j.clineuro.2021.106565

12. Sakai D, Schol J, Foldager CB, Sato M, Watanabe M. Rege­nerative technologies to bed side: evolving the regulatory framework. J Orthop Translat. 2017;9:1–7. https://doi.org/10.1016/j.jot.2017.02.001

13. Najar M, Melki R, Khalife F, Lagneaux L, Bouhtit F, Moussa Agha D, et al. Therapeutic mesenchymal stem/stromal cells: value, challenges and optimization. Front Cell Dev Biol. 2022;9:716853. https://doi.org/10.3389/fcell.2021.716853

14. Brockmann I, Ehrenpfordt J, Sturmheit T, Brandenburger M, Kruse C, Zille M, et al. Skin-derived stem cells for wound treatment using cultured epidermal autografts: clinical applications and challenges. Stem Cells Int. 2018;2018:4623615. https://doi.org/10.1155/2018/4623615

15. Melnikova EV, Merkulova OV, Merkulov VA. Clinical trials for cellular therapy products: conclusions reached by foreign regulatory bodies. Russian Journal of Transplantology and Artificial Organs. 2020;22(2):139–50 (In Russ.). https://doi.org/10.15825/1995-1191-2020-2-139-150

16. Pavlova VYu, Livadnyi ES. CAR-T technology and new opportunities for tumor treatment. Clinical Oncohematology. 2021;14(1):149–56 (In Russ.). https://doi.org/10.21320/2500-2139-2021-14-1-149-156

17. Grissenberger S, Salzer B, Pascoal S, Wenninger-­Weinzierl A, Lehner M, Distel M. Chapter 8 — Preclinical testing of CAR T cells in zebrafish xenografts. Method Cell Biol. 2022;167:133–47. https://doi.org/10.1016/bs.mcb.2021.07.002

18. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. https://doi.org/10.1038/s41408-021-00459-7

19. Gavrilina OA, Galstyan GM, Shchekina AE, Kotova ES, Maschan MA, Troitskaya VV, et al. Chimeric antigen receptor T-cell therapy in adult patients with B-cell lymphoproliferative diseases. Russian Journal of Hematology and Transfusiology. 2022;67(1):8–28 (In Russ.). https://doi.org/10.35754/0234-5730-2022-67-1-8-28

20. Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germe­raad WTV. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hemat Oncol. 2021;14(1):73. https://doi.org/10.1186/s13045-021-01083-5

21. Habib S, Tariq SM, Tariq M. Chimeric antigen receptor-natural killer cells: the future of cancer immunotherapy. Ochsner J. 2019;19(3):186–7. https://doi.org/10.31486/toj.19.0033

22. Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252–60. https://doi.org/10.1056/NEJMoa2031054

23. Kiseleva YaYu, Shishkin AM, Ivanov AV, Kulinich TM, Bozhenko VK. CAR T-cell therapy of solid tumors: promising approaches to modulating antitumor activity of CAR T cells. Bulletin of RSMU. 2019;(5):5–13 (In Russ.). https://doi.org/10.24075/vrgmu.2019.066

24. Kwon SG, Kwon YW, Lee TW, Park GT, Kim JH. Recent advances in stem cell therapeutics and tissue engineering strategies. Biomater Res. 2018;22:36. https://doi.org/10.1186/s40824-018-0148-4

25. Pashtaev NP, ed. Modern methods of diagnosis and surgical treatment of keratoconus. Cheboksary; 2017 (In Russ.). EDN: IXHREG

26. Gibson ALF, Holmes JH 4th, Shupp JW, Smith D, Joe V, Carson J, et al. A phase 3, open-label, controlled, randomized, multicenter trial evaluating the efficacy and safety of StrataGraft® construct in patients with deep partial-thickness thermal burns. Burns. 2021;47(5):1024–37. https://doi.org/10.1016/j.burns.2021.04.021

27. Heng CHY, Snow M, Dave LYH. Single-stage arthroscopic cartilage repair with injectable scaffold and BMAC. Arthrosc Tech. 2021;10(3):e751–6. https://doi.org/10.1016/j.eats.2020.10.065

28. Pathak S, Chaudhary D, Reddy KR, Acharya KKV, Desai SM. Efficacy and safety of CARTIGROW® in patients with articular cartilage defects of the knee joint: a four year prospective studys. Int Orthop. 2022;46(6):1313–21. https://doi.org/10.1007/s00264-022-0536

29. Hmadcha A, Martin-Montalvo A, Gauthier BR, Soria B, Capilla-Gonzalez V. Therapeutic potential of mesenchymal stem cells for cancer therapy. Front Bioeng Biotechnol. 2020;8:43. https://doi.org/10.3389/fbioe.2020.00043

30. Gimble JM, Katz AJ, Bunnel BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2014;100(9):1249–60. https://doi.org/10.1161/01.RES.0000265074.83288.09

31. Howard D, Buttery LD, Shakesheff KM, Roberts SJ. Tissue engineering: strategies, stem cells and scaffolds. J Anat. 2008;213(1):66–72. https://doi.org/10.1111/j.1469-7580.2008.00878.x

32. Rachinskaya OA, Melnikova EV, Merkulov VA. Current trends and risks associated with the use of therapies based on genome editing. Biological Products. Prevention, Diagnosis, Treatment. 2023;23(3):247–61 (In Russ.). https://doi.org/10.30895/2221-996X-2023-23-3-247-261