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Проблемы клинических испытаний эффективности клеточной терапии сегодня

https://doi.org/10.18699/SSMJ20210102

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Аннотация

Основной целью статьи является дискуссия на тему эффективности клеточной терапии. Нами проанализированы, на примере некоторых направлений, тенденции в проведении клинических испытаний по определению эффективности клеточной терапии. В работе обсуждаются вопросы концептуальных подходов применения клеточной терапии, ее клинических результатов, выявленных проблем.

Об авторах

А. Г. Попандопуло
Институт неотложной и восстановительной хирургии им. В.К. Гусака Министерства здравоохранения Донецкой Народной Республики
Украина

Андрей Геннадьевич Попандопуло, д.м.н., проф.

283045, г. Донецк, Ленинский просп., 47



В. В. Турчин
Институт неотложной и восстановительной хирургии им. В.К. Гусака Министерства здравоохранения Донецкой Народной Республики
Украина

Виктор Васильевич Турчин

283045, г. Донецк, Ленинский просп., 47



М. В. Солопов
Институт неотложной и восстановительной хирургии им. В.К. Гусака Министерства здравоохранения Донецкой Народной Республики
Украина

Максим Витальевич Солопов

283045, г. Донецк, Ленинский просп., 47



В. В. Буше
Институт неотложной и восстановительной хирургии им. В.К. Гусака Министерства здравоохранения Донецкой Народной Республики
Украина

Виктория Валерьевна Буше, к.б.н.

283045, г. Донецк, Ленинский просп., 47



Список литературы

1. Abati E., Bresolin N., Comi G., Corti S. Advances, challenges, and perspectives in translational stem cell therapy for amyotrophic lateral sclerosis. Mol. Neurobiol. 2019; 56 (10): 6703–6715. doi: 10.1007/s12035-019-1554-x

2. O’Connor N.E., Mulliken J.B., Banks-Schlegel S., Kehinde O., Green H. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet. 1981; 317: 75–78.

3. Bozdağ S.C., Yüksel M.K., Demirer T. Adult stem cells and medicine. Adv. Exp. Med. Biol. 2018; 1079: 17–36. doi: 10.1007/5584_2018_184

4. Morgan R.A., Gray D., Lomova A., Kohn D.B. Hematopoietic stem cell gene therapy: progress and lessons learned. Cell Stem Cell. 2017; 21 (5): 574–590. doi: 10.1016/j.stem.2017.10.010

5. Shapiro A.M.J., Pokrywczynska M., Ricordi C. Clinical pancreatic islet transplantation. Nat. Rev. Endocrinol. 2017; 13 (5): 268–277. doi: 10.1038/nrendo.2016.178

6. Banerjee M., Bolli R., Hare J. Clinical studies of cell therapy in cardiovascular medicine: recent developments and future directions. Circ. Res. 2018; 123 (2): 266–287. doi: 10.1161/CIRCRESAHA.118.311217

7. Sugaya K., Vaidya M. Stem cell therapies for neurodegenerative diseases. Adv. Exp. Med. Biol. 2018; 1056: 61–84. doi: 10.1007/978-3-319-74470-4_5

8. Yasuhara T., Kameda M., Sasaki T., Tajiri N., Date I. Cell therapy for Parkinson’s disease. Cell Transplant. 2017; 26 (9): 1551–1559. doi: 10.1177/0963689717735411

9. Moradi S., Mahdizadeh H., Šarić T., Kim J., Harati J., Shahsavarani H., Greber B., Moore J.B. Research and therapy with induced pluripotent stem cells (iPSC): social, legal, and ethical considerations. Stem Cell Res. Ther. 2019; 10 (1): 341. doi: 10.1186/s13287019-1455-y

10. Liang X., Ding Y., Zhang Y., Tse H.-F., Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transplant. 2014; 23 (9): 1045–1059. doi: 10.3727/096368913X667709

11. Burdon T.J., Paul A., Noiseux N., Prakash S., Shum-Tim D. Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. Bone Marrow Res. 2011; 2011: 207326. doi: 10.1155/2011/207326

12. Regmi S., Pathak S., Kim J.O., Yong C.S., Jeong J.H. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur. J. Cell Biol. 2019; 98 (5-8): 151041. doi: 10.1016/j.ejcb.2019.04.002

13. Locatelli F., Algeri M., Trevisan V., Bertaina A. Remestemcel L for the treatment of graft versus host disease. Expert Rev. Clin. Immunol. 2017; 13 (1): 43–56. doi: 10.1080/1744666X.2016.1208086

14. Kurtzberg J., Prockop S., Teira P., Bittencourt H., Lewis V., Chan K.W., Horn B., Yu L., Talano J.A., Nemecek E., Mills C.R., Chaudhury S. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol. Blood Marrow Transplant. 2014; 20 (2): 229–235. doi: 10.1016/j.bbmt.2013.11.001

15. Kidd S., Spaeth E., Dembinski J.L., Dietrich M., Watson K., Klopp A., Battula V.L., Weil M., Andreeff M., Marini F.C. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells. 2009; 27 (10): 2614–2623. doi: 10.1002/stem.187

16. Hagenhoff A., Bruns C.J., Zhao Y., von Lüttichau I., Niess H., Spitzweg C., Nelson P.J. Harnessing mesenchymal stem cell homing as an anticancer therapy. Expert Opin. Biol. Ther. 2016; 16 (9): 1079–1092. doi: 10.1080/14712598.2016.1196179

17. Menasche P., Hagege A.A., Scorsin M., Pouzet B., Desnos M., Duboc D., Schwartz K., Vilquin J.T., Marolleau J.P. Myoblast transplantation for heart failure. Lancet. 2001; 357 (9252): 279–280. doi: 10.1016/S0140-6736(00)03617-5

18. Mathur A., Arnold R., Assmus B., Bartunek J., Belmans A., Bönig H., Crea F., Dimmeler S., Dowlut S., Fernandez-Aviles F., Galinanes M., Garcia-Dorado D., Hartikainen J., Hill J., Hogardt-Noll A., Homsy C., Janssens S., Kala P., Kastrup J., Martin J., Menasche P., Miklik R., Mozid A., San Roman J.A., Sanz-Ruiz R., Tendera M., Wojakowski W., Ylä-Herttuala S., Zeiher A. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial. Eur. J. Heart Fail. 2017; 19 (11): 1545–1550. doi: 10.1002/ejhf.829

19. Bartunek J., Terzic A., Davison B.A., Filippatos G.S., Radovanovic S., Beleslin B., Merkely B., Musialek P., Wojakowski W., Andreka P., … CHART Program. Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial. Eur. Heart J. 2017; 38: 648–660. doi: 10.1093/eurheartj/ehw543

20. Perin E.C., Willerson J.T., Pepine C.J., Henry T.D., Ellis S.G., Zhao D.X., Silva G.V., Lai D., Thomas J.D., Kronenberg M.W., Martin A.D., Anderson R.D., Traverse J.H., Penn M.S., Anwaruddin S., Hatzopoulos A.K., Gee A.P., Taylor D.A., Cogle C.R., Smith D., Westbrook L., Chen J., Handberg E., Olson R.E., Geither C., Bowman S., Francescon J., Baraniuk S., Piller L.B., Simpson L.M., Loghin C., Aguilar D., Richman S., Zierold C., Bettencourt J., Sayre S.L., Vojvodic R.W., Skarlatos S.I., Gordon D.J., Ebert R.F., Kwak M., Moye L.A., Simari R.D.; Cardiovascular Cell Therapy Research Network (CCTRN). Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUSCCTRN trial. JAMA. 2012; 307 (16): 1717–1726. doi: 10.1001/jama.2012.418

21. Van Berlo J.H., Kanisicak O., Maillet M., Vagnozzi R.J., Karch J., Lin S.C., Middleton R.C., Marban E., Molkentin J.D. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014; 509 (7500): 337–341. doi: 10.1038/nature13309

22. Hatzistergos K.E., Quevedo H., Oskouei B.N., Hu Q., Feigenbaum G.S., Margitich I.S., Mazhari R., Boyle A.J., Zambrano J.P., Rodriguez J.E., Dulce R., Pattany P.M., Valdes D., Revilla C., Heldman A.W., McNiece I., Hare J.M. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ. Res. 2010; 107 (7): 913–922. doi: 10.1161/CIRCRESAHA.110.222703

23. Zhang S., Wang D., Estrov Z., Raj S., Willerson J.T., Yeh E.T. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo. Circulation. 2004; 110 (25): 3803–3807. doi: 10.1161/01.CIR.0000150796.18473.8E

24. Quevedo H.C., Hatzistergos K.E., Oskouei B.N., Feigenbaum G.S., Rodriguez J.E., Valdes D., Pattany P.M., Zambrano J.P., Hu Q., McNiece I., Heldman A.W., Hare J.M. Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity. Proc. Natl. Acad. Sci. USA. 2009; 106 (33): 1402214027. doi: 10.1073/pnas.0903201106

25. Mayourian J., Cashman T.J., Ceholski D.K., Johnson B.V., Sachs D., Kaji D.A., Sahoo S., Hare J.M., Hajjar R.J., Sobie E.A., Costa K.D. Experimental and computational insight into human mesenchymal stem cell paracrine signaling and heterocellular coupling effects on cardiac contractility and arrhythmogenicity. Circ. Res. 2017; 121 (4): 411–423. doi: 10.1161/CIRCRESAHA.117.310796

26. Golpanian S., Wolf A., Hatzistergos K.E., Hare J.M. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol. Rev. 2016; 96 (3): 1127–1168. doi:10.1152/physrev.00019.2015

27. Xiao C., Zhou S., Liu Y., Hu H. Efficacy and safety of bone marrow cell transplantation for chronic ischemic heart disease: a meta-analysis. Med. Sci. Monit. 2014; 20: 1768–1777. doi: 10.12659/MSM.892047

28. Xiao W., Guo S., Gao C., Dai G., Gao Y., Li M., Wang X., Hu D. A randomized comparative study on the efficacy of intracoronary infusion of autologous bone marrow mononuclear cells and mesenchymal stem cells in patients with dilated cardiomyopathy. Int. Heart J. 2017; 58 (2): 238–244. doi: 10.1536/ihj.16-328

29. Quyyumi A.A., Vasquez A., Kereiakes D.J., Klapholz M., Schaer G.L., Abdel-Latif A., Frohwein S., Henry T.D., Schatz R.A., Dib N., Toma C., Davidson C.J., Barsness G.W., Shavelle D.M., Cohen M., Poole J., Moss T., Hyde P., Kanakaraj A.M., Druker V., Chung A., Junge C., Preti R.A., Smith R.L., Mazzo D.J., Pecora A., Losordo D.W. PreSERVE-AMI: a randomized, double-blind, placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in patients with left ventricular dysfunction post STEMI. Circ. Res. 2017; 120 (2): 324–331. doi: 10.1161/CIRCRESAHA.115.308165

30. Henry T.D., Losordo D.W., Traverse J.H., Schatz R.A., Jolicoeur E.M., Schaer G.L., Clare R., Chiswell K., White C.J., Fortuin F.D., Kereiakes D.J., Zeiher A.M., Sherman W., Hunt A.S., Povsic T.J. Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur. Heart J. 2018; 39 (23): 2208–2216. doi: 10.1093/eurheartj/ehx764

31. Hare J.M., Traverse J.H., Henry T.D., Dib N., Strumpf R.K., Schulman S.P., Gerstenblith G., DeMaria A.N., Denktas A.E., Gammon R.S, Hermiller J.B.Jr, Reisman M.A., Schaer G.L., Sherman W. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J. Am. Coll. Cardiol. 2009; 54 (24): 2277–2286. doi: 10.1016/j.jacc.2009.06.055

32. Gao L.R., Chen Y., Zhang N.K., Yang X.L., Liu H.L., Wang Z.G., Yan X.Y., Wang Y., Zhu Z.M., Li T.C., Wang L.H., Chen H.Y., Chen Y.D., Huang C.L., Qu P., Yao C., Wang B., Chen G.H., Wang Z.M., Xu Z.Y., Bai J., Lu D., Shen Y.H., Guo F., Liu M.Y., Yang Y., Ding Y.C., Yang Y., Tian H.T., Ding Q.A., Li L.N., Yang X.C., Hu X. Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med. 2015; 13: 162. doi: 10.1186/s12916-015-0399-z

33. Bartolucci J., Verdugo F.J., Gonzalez P.L., Larrea R.E., Abarzua E., Goset C., Rojo P., Palma I., Lamich R., Pedreros P.A., Valdivia G., Lopez V.M., Nazzal C., Alcayaga-Miranda F., Cuenca J., Brobeck M.J., Patel A.N., Figueroa F.E., Khoury M. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]). Circ. Res. 2017; 121 (10): 1192–1204. doi: 10.1161/CIRCRESAHA.117.310712

34. Hare J.M., Fishman J.E., Gerstenblith G., DiFede Velazquez D.L., Zambrano J.P., Suncion V.Y., Tracy M., Ghersin E., Johnston P.V., Brinker J.A., Breton E., Davis-Sproul J., Schulman I.H., Byrnes J., Mendizabal A.M., Lowery M.H., Rouy D., Altman P., Wong Po Foo C., Ruiz P., Amador A., da Silva J., McNiece I.K., Heldman A.W., George R., Lardo A. Comparison of allogeneic vs autologous bone marrowderived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012; 308 (22): 2369–2379. doi: 10.1001/jama.2012.25321

35. Hare J.M., DiFede D.L., Rieger A.C., Florea V., Landin A.M., El-Khorazaty J., Khan A., Mushtaq M., Lowery M.H., Byrnes J.J., Hendel R.C., Cohen M.G., Alfonso C.E., Valasaki K., Pujol M.V., Golpanian S., Ghersin E., Fishman J.E., Pattany P., Gomes S.A., Delgado C., Miki R., Abuzeid F., Vidro-Casiano M., Premer C., Medina A., Porras V., Hatzistergos K.E., Anderson E., Mendizabal A., Mitrani R., Heldman A.W. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM Trial. J. Am. Coll. Cardiol. 2017; 69 (5): 526–537. doi: 10.1016/j.jacc.2016.11.009

36. See F., Seki T., Psaltis P.J., Sondermeijer H.P., Gronthos S., Zannettino A.C., Govaert K.M., Schuster M.D., Kurlansky P.A., Kelly D.J., Krum H., Itescu S. Therapeutic effects of human STRO-3-selected mesenchymal precursor cells and their soluble factors in experimental myocardial ischemia. J. Cell Mol. Med. 2011; 15 (10): 2117–2129. doi: 10.1111/j.15824934.2010.01241.x

37. Henry T.D., Pepine C.J., Lambert C.R., Traverse J.H., Schatz R., Costa M., Povsic T.J., Anderson D.R., Willerson J.T., Kesten S., Perin E.C. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc. Interv. 2017; 89 (2): 169–177. doi: 10.1002/ccd.26601

38. Sahoo S., Losordo D.W. Exosomes and cardiac repair after myocardial infarction. Circ. Res. 2014; 114 (2): 333–344. doi:10.1161/CIRCRESAHA.114.300639

39. Keith M.C., Bolli R. «String theory» of c-kit(pos) cardiac cells: a new paradigm regarding the nature of these cells that may reconcile apparently discrepant results. Circ. Res. 2015; 116 (7): 1216–1230. doi:10.1161/CIRCRESAHA.116.305557

40. Chugh A.R., Beache G.M., Loughran J.H., Mewton N., Elmore J.B., Kajstura J., Pappas P., Tatooles A., Stoddard M.F., Lima J.A., Slaughter M.S., Anversa P., Bolli R. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation. 2012; 126 (11, Suppl. 1): 54–64. doi: 10.1161/CIRCULATIONAHA.112.092627

41. The Lancet Editors. Retraction-Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): Initial results of a randomised phase 1 trial. Lancet. 2019; 393 (10176): 1084. doi: 10.1016/S01406736(19)30542-2

42. Makkar R.R., Smith R.R., Cheng K., Malliaras K., Thomson L.E., Berman D., Czer L.S., Marban L., Mendizabal A., Johnston P.V., Russell S.D., Schuleri K.H., Lardo A.C., Gerstenblith G., Marban E. Intracoronary Cardiosphere-Derived Cells for Heart Regeneration After Myocardial Infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012; 379 (9819): 895–904. doi: 10.1016/S0140-6736(12)60195-0

43. Kapelios C.J., Nanas J.N., Malliaras K. Allogeneic cardiosphere-derived cells for myocardial regeneration: current progress and recent results. Future Cardiol. 2016; 12 (1): 87–100. doi: 10.2217/fca.15.72

44. Nakamura K., Murry C.E. Function follows form – a review of cardiac cell therapy. Circ. J. 2019; 83 (12): 2399–2412. doi: 10.1253/circj.CJ-19-0567

45. Behfar A., Yamada S., Crespo-Diaz R., Nesbitt J.J., Rowe L.A., Perez-Terzic C., Gaussin V., Homsy C., Bartunek J., Terzic A. Guided cardiopoiesis enhances therapeutic benefit of bone marrow human mesenchymal stem cells in chronic myocardial infarction. J. Am. Coll. Cardiol. 2010; 56 (9): 721–734. doi:10.1016/j.jacc.2010.03.066

46. Teerlink J.R., Metra M., Filippatos G.S., Davison B.A., Bartunek J., Terzic A., Gersh B.J., Povsic T.J., Henry T.D., Alexandre B., Homsy C., Edwards C., Seron A., Wijns W., Cotter G., CHART Investigators. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur. J. Heart Fail. 2017; 19 (11): 1520–1529. doi: 10.1002/ejhf.898

47. Stevens K.R., Murry C.E. Human pluripotent stem cell-derived engineered tissues: Clinical considerations. Cell Stem Cell. 2018; 22 (3): 294–297. doi: 10.1016/j.stem.2018.01.015

48. Romagnuolo R., Masoudpour H., PortaSanchez A., Qiang B., Barry J., Laskary A., Qi X., Masse S., Magtibay K., Kawajiri H., Wu J., Valdman Sadikov T., Rothberg J., Panchalingam K.M., Titus E., Li R.K., Zandstra P.W., Wright G.A., Nanthakumar K., Ghugre N.R., Keller G., Laflamme M.A. Human embryonic stem cell-derived cardiomyocytes regenerate the infarcted pig heart but induce ventricular tachyarrhythmias. Stem Cell Rep. 2019; 12 (5): 967–981. doi:10.1016/j.stemcr.2019.04.005

49. Menasche P., Vanneaux V., Hagege A., Bel A., Cholley B., Parouchev A., Cacciapuoti I., Al-Daccak R., Benhamouda N., Blons H., Agbulut O., Tosca L., Trouvin J.H., Fabreguettes J.R., Bellamy V., Charron D., Tartour E., Tachdjian G., Desnos M., Larghero J. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 2018; 71 (4): 429–438. doi: 10.1016/j.jacc.2017.11.047

50. Shiba Y., Gomibuchi T., Seto T., Wada Y., Ichimura H., Tanaka Y., Ogasawara T., Okada K., Shiba N., Sakamoto K., Ido D., Shiina T., Ohkura M., Nakai J., Uno N., Kazuki Y., Oshimura M., Minami I., Ikeda U. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016; 538 (7625): 388–391. doi: 10.1038/nature19815

51. Kawamura M., Miyagawa S., Fukushima S., Saito A., Miki K., Ito E., Sougawa N., Kawamura T., Daimon T., Shimizu T., Okano T., Toda K., Sawa Y. Enhanced survival of transplanted human induced pluripotent stem cell-derived cardiomyocytes by the combination of cell sheets with the pedicled omental flap technique in a porcine heart. Circulation. 2013; 128 (11 Suppl 1): 87–94. doi: 10.1161/CIRCULATIONAHA.112.000366

52. Karantalis V., Suncion-Loescher V.Y., Bagno L., Golpanian S., Wolf A., Sanina C., Premer C., Kanelidis A.J., McCall F., Wang B., Balkan W., Rodriguez J., Rosado M., Morales A., Hatzistergos K., Natsumeda M., Margitich I., Schulman I.H., Gomes S.A., Mushtaq M., DiFede D.L., Fishman J.E., Pattany P., Zambrano J.P., Heldman A.W., Hare J.M. Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. J. Am. Coll. Cardiol. 2015; 66: 19901999. doi: 10.1016/j.jacc.2015.08.879

53. Bolli R., Hare J.M., March K.L., Pepine C.J., Willerson J.T., Perin E.C., Yang P.C., Henry T.D., Traverse J.H., Mitrani R.D., Khan A., HernandezSchulman I., Taylor D.A., DiFede D.L., Lima J.A.C., Chugh A., Loughran J., Vojvodic R.W., Sayre S.L., Bettencourt J., Cohen M., Moye L., Ebert R.F., Simari R.D.; Cardiovascular Cell Therapy Research Network (CCTRN). Rationale and design of the CONCERT-HF (Combination of mesenchymal and c-kit(+) cardiac stem cells as regenerative therapy for heart failure) trial. Circ. Res. 2018; 122: 1703–1715. doi: 10.1161/CIRCRESAHA.118.312978

54. Shipounova I.N., Petinati N.A., Bigildeev A.E., Zezina E.A., Drize N.I., Kuzmina L.A., Parovichnikova E.N., Savchenko V.G. Analysis of results of acute graft-versus-host disease prophylaxis with donor multipotent mesenchymal stromal cells in patients with hemoblastoses after allogeneic bone marrow transplantation. Biochemistry (Moscow). 2014; 79 (12): 1363–1370. doi: 10.1134/S0006297914120104

55. Zhao L., Chen S., Yang P., Cao H., Li L. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graftversus-host disease. Stem Cell Res. Ther. 2019; 10 (1): 182. doi: 10.1186/s13287-019-1287-9

56. Laport G.G., Sheehan K., Baker J., Armstrong R., Wong R.M., Lowsky R., Johnston L.J., Shizuru J.A., Miklos D., Arai S., Benjamin J.E., Weng W.K., Negrin R.S. Adoptive immunotherapy with cytokineinduced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 2011; 17 (11): 1679–1687. doi: 10.1016/j.bbmt.2011.05.012

57. Jiang J.T., Shen Y.P., Wu C.P., Zhu Y.B., Wei W.X., Chen L.J., Zheng X., Sun J., Lu B.F., Zhang X.G. Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J. Gastroenterol. 2010; 16 (48): 6155–6162. doi: 10.3748/wjg.v16.i48.6155

58. Liu L., Zhang W., Qi X., Li H., Yu J., Wei S., Hao X., Ren X. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin. Cancer Res. 2012; 18 (6): 1751–1759. doi: 10.1158/1078-0432.CCR-11-2442

59. Parkhurst M.R., Riley J.P., Dudley M.E., Rosenberg S.A. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin. Cancer Res. 2011; 17 (19): 6287–6297. doi: 10.1158/10780432.CCR-11-1347

60. Rohaan M.W., Wilgenhof S., Haanen J.B.A.G. Adoptive cellular therapies: the current landscape. Virchows Arch. 2019; 474 (4): 449–461. doi: 10.1007/s00428-018-2484-0

61. Stevanović S., Draper L.M., Langhan M.M., Campbell T.E., Kwong M.L., Wunderlich J.R., Dudley M.E., Yang J.C., Sherry R.M., Kammula U.S., Restifo N.P., Rosenberg S.A., Hinrichs C.S. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 2015; 33 (14): 1543–1550. doi: 10.1200/JCO.2014.58.9093

62. Lee H.J., Kim Y.A., Sim C.K., Heo S.H., Song I.H., Park H.S., Park S.Y., Bang W.S., Park I.A., Lee M., Lee J.H., Cho Y.S., Chang S., Jung J., Kim J., Lee S.B., Kim S.Y., Lee M.S., Gong G. Expansion of tumor-infiltrating lymphocytes and their potential for application as adoptive cell transfer therapy in human breast cancer. Oncotarget. 2017; 8 (69): 113345113359. doi: 10.18632/oncotarget.23007

63. Andersen R., Westergaard M.C.W., Kjeldsen J.W., Müller A., Pedersen N.W., Hadrup S.R., Met Ö., Seliger B., Kromann-Andersen B., Hasselager T., Donia M., Svane I.M. T-cell responses in the microenvironment of primary renal cell carcinoma-implications for adoptive cell therapy. Cancer Immunol. Res. 2018; 6 (2): 222–235. doi: 10.1158/2326-6066.CIR-17-0467

64. Ben-Avi R., Farhi R., Ben-Nun A., Gorodner M., Greenberg E., Markel G., Schachter J., Itzhaki O., Besser M.J. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol. Immunother. 2018; 67 (8): 1221–1230. doi: 10.1007/s00262-0182174-4

65. Rosenberg S.A., Yang J.C., Sherry R.M., Kammula U.S., Hughes M.S., Phan G.Q., Citrin D.E., Restifo N.P., Robbins P.F., Wunderlich J.R., Morton K.E., Laurencot C.M., Steinberg S.M., White D.E., Dudley M.E. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 2011; 17 (13): 4550–4557. doi: 10.1158/1078-0432.CCR-110116

66. Nguyen L.T., Saibil S.D., Sotov V., Le M.X., Khoja L., Ghazarian D., Bonilla L., Majeed H., Hogg D., Joshua A.M., Crump M., Franke N., Spreafico A., Hansen A., Al-Habeeb A., Leong W., Easson A., Reedijk M., Goldstein D.P., McCready D., Yasufuku K., Waddell T., Cypel M., Pierre A., Zhang B., Boross-Harmer S., Cipollone J., Nelles M., Scheid E., Fyrsta M., Lo C.S., Nie J., Yam J.Y., Yen P.H., Gray D., Motta V., Elford A.R., DeLuca S., Wang L., Effendi S., Ellenchery R., Hirano N., Ohashi P.S., Butler M.O. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol. Immunother. 2019; 68 (5): 773–785. doi: 10.1007/s00262-019-02307-x

67. Goff S.L., Dudley M.E., Citrin D.E., Somerville R.P., Wunderlich J.R., Danforth D.N., Zlott D.A., Yang J.C., Sherry R.M., Kammula U.S., Klebanoff C.A., Hughes M.S., Restifo N.P., Langhan M.M., Shelton T.E., Lu L., Kwong M.L., Ilyas S., Klemen N.D., Payabyab E.C., Morton K.E., Toomey M.A., Steinberg S.M., White D.E., Rosenberg S.A. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J. Clin. Oncol. 2016; 34 (20): 2389–2397. doi: 10.1200/JCO.2016.66.7220

68. June C.H., O’Connor R.S., Kawalekar O.U., Ghassemi S., Milone M.C. CAR T cell immunotherapy for human cancer. Science. 2018; 359 (6382): 13611365. doi: 10.1126/science.aar6711

69. Johnson L.A., Morgan R.A., Dudley M.E., Cassard L., Yang J.C., Hughes M.S., Kammula U.S., Royal R.E., Sherry R.M., Wunderlich J.R., Lee C.C., Restifo N.P., Schwarz S.L., Cogdill A.P., Bishop R.J., Kim H., Brewer C.C., Rudy S.F., VanWaes C., Davis J.L., Mathur A., Ripley R.T., Nathan D.A., Laurencot C.M., Rosenberg S.A. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009; 114 (3): 535–546. doi: 10.1182/blood-2009-03-211714

70. Robbins P.F., Morgan R.A., Feldman S.A., Yang J.C., Sherry R.M., Dudley M.E., Wunderlich J.R., Nahvi A.V., Helman L.J., Mackall C.L., Kammula U.S., Hughes M.S., Restifo N.P., Raffeld M., Lee C.C., Levy C.L., Li Y.F., El-Gamil M., Schwarz S.L., Laurencot C., Rosenberg S.A. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 2011; 29 (7): 917–924. doi: 10.1200/JCO.2010.32.2537

71. Morgan R.A., Chinnasamy N., Abate-Daga D., Gros A., Robbins P.F., Zheng Z., Dudley M.E., Feldman S.A., Yang J.C., Sherry R.M., Phan G.Q., Hughes M.S., Kammula U.S., Miller A.D., Hessman C.J., Stewart A.A., Restifo N.P., Quezado M.M., Alimchandani M., Rosenberg A.Z., Nath A., Wang T., Bielekova B., Wuest S.C., Akula N., McMahon F.J., Wilde S., Mosetter B., Schendel D.J., Laurencot C.M., Rosenberg S.A. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 2013; 36 (2): 133–151. doi: 10.1097/CJI.0b013e3182829903

72. Parkhurst M.R., Yang J.C., Langan R.C., Dudley M.E., Nathan D.A., Feldman S.A., Davis J.L., Morgan R.A., Merino M.J., Sherry R.M., Hughes M.S., Kammula U.S., Phan G.Q., Lim R.M., Wank S.A., Restifo N.P., Robbins P.F., Laurencot C.M., Rosenberg S.A. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 2011; 19 (3): 620–626. doi: 10.1038/mt.2010.272

73. Almond L.M., Charalampakis M., Ford S.J., Gourevitch D., Desai A. Myeloid sarcoma: presentation, diagnosis, and treatment. Clin. Lymphoma Myeloma Leuk. 2017; 17 (5): 263–267. doi: 10.1016/j.clml.2017.02.027

74. Locke F.L., Neelapu S.S., Bartlett N.L., Siddiqi T., Chavez J.C., Hosing C.M., Ghobadi A., Budde L.E., Bot A., Rossi J.M., Jiang Y., Xue A.X., Elias M., Aycock J., Wiezorek J., Go W.Y. Phase 1 Results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 2017; 25 (1): 285-295. doi: 10.1016/j.ymthe.2016.10.020

75. Bach P.B., Giralt S.A., Saltz L.B. FDA approval of tisagenlecleucel: promise and complexities of a $475 000 cancer drug. JAMA. 2017; 318 (19): 18611862. doi: 10.1001/jama.2017.15218

76. Fala L. Yescarta (Axicabtagene Ciloleucel) second CAR T-cell therapy approved for patients with certain types of large B-cell lymphoma. Am. Health Drug Benefits. 2018; 11: 109–111.

77. Mirzaei H.R., Rodriguez A., Shepphird J., Brown C.E., Badie B. Chimeric antigen receptors T cell therapy in solid tumor: challenges and clinical applications. Front. Immunol. 2017; 8: 1850. doi: 10.3389/fimmu.2017.01850

78. Mohanty R., Chowdhury C.R., Arega S., Sen P., Ganguly P., Ganguly N. CAR T cell therapy: A new era for cancer treatment (Review). Oncol. Rep. 2019; 42 (6): 2183–2195. doi: 10.3892/or.2019.7335

79. Kebriaei P. CAR T-cell therapies: Overcoming the challenges and new strategies. Clin. Lymphoma Myeloma Leuk. 2017; 17 (Suppl 2): 74–78.

80. Bonifant C.L., Jackson H.J., Brentjens R.J., Curran K.J. Toxicity and management in CAR T-cell therapy. Mol. Ther. Oncolytics. 2016; 3: 16011. doi: 10.1038/mto.2016.11

81. Di Stasi A., Tey S.K., Dotti G., Fujita Y., Kennedy-Nasser A., Martinez C., Straathof K., Liu E., Durett A.G., Grilley B., Liu H., Cruz C.R., Savoldo B., Gee A.P., Schindler J., Krance R.A., Heslop H.E., Spencer D.M., Rooney C.M., Brenner M.K. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 2011; 365 (18): 1673–1683. doi: 10.1056/NEJMoa1106152

82. Linette G.P., Stadtmauer E.A., Maus M.V., Rapoport A.P., Levine B.L., Emery L., Litzky L., Bagg A., Carreno B.M., Cimino P.J., Binder-Scholl G.K., Smethurst D.P., Gerry A.B., Pumphrey N.J., Bennett A.D., Brewer J.E., Dukes J., Harper J., Tayton-Martin H.K., Jakobsen B.K., Hassan N.J., Kalos M., June C.H. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013; 122 (6): 863–871. doi: 10.1182/blood2013-03-490565

83. Linnemann C., Schumacher T.N., Bendle G.M. T-cell receptor gene therapy: critical parameters for clinical success. J. Invest. Dermatol. 2011; 131 (9): 1806–1816. doi: 10.1038/jid.2011.160

84. Morgan R.A., Dudley M.E., Wunderlich J.R., Hughes M.S., Yang J.C., Sherry R.M., Royal R.E., Topalian S.L., Kammula U.S., Restifo N.P., Zheng Z., Nahvi A., de Vries C.R., Rogers-Freezer L.J., Mavroukakis S.A., Rosenberg S.A. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006; 314 (5796): 126–129. doi: 10.1126/science.1129003

85. Haanen J.B. Immunotherapy of melanoma. EJC Suppl. 2013; 11 (2): 97–105. doi: 10.1016/j.ejcsup.2013.07.013

86. Palucka K., Banchereau J. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer. 2012; 12 (4): 265–277. doi: 10.1038/nrc3258

87. Widén K., Mozaffari F., Choudhury A., Mellstedt H. Overcoming immunosuppressive mechanisms. Ann. Oncol. 2008; 19 (Suppl 7): 241–247. doi: 10.1093/annonc/mdn459

88. Титов К.С., Демидов Л.В., Шубина И.Ж., Хайленко В.А., Киселевский М.В., Вихрова А.С. Технологии клеточной иммунотерапии в лечении больных со злокачественными новообразованиями. Вестн. РГМУ. 2014; (1): 42–47.

89. Bansal A., Pandey M.K., Demirhan Y.E., Nesbitt J.J., Crespo-Diaz R.J., Terzic A., Behfar A., DeGrado T.R. Novel (89)Zr cell labeling approach for PET-based cell trafficking studies. EJNMMI Res. 2015; 5: 19. doi: 10.1186/s13550-015-0098-y

90. Levy O., Brennen W.N., Han E., Rosen D.M., Musabeyezu J., Safaee H., Ranganath S., Ngai J., Heinelt M., Milton Y., Wang H., Bhagchandani S.H., Joshi N., Bhowmick N., Denmeade S.R., Isaacs J.T., Karp J.M. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer. Biomaterials. 2016; 91: 140–150. doi: 10.1016/j.biomaterials.2016.03.023

91. Krueger T.E.G., Thorek D.L.J., Denmeade S.R., Isaacs J.T., Brennen W.N. Concise review: mesenchymal stem cell-based drug delivery: the good, the bad, the ugly, and the promise. Stem Cells Transl. Med. 2018; 7 (9): 651–663. doi: 10.1002/sctm.18-0024

92. Dembinski J.L., Spaeth E.L., Fueyo J., GomezManzano C., Studeny M., Andreeff M., Marini F.C. Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells. Cancer Gene Ther. 2010; 17 (4): 289–297. doi: 10.1038/cgt.2009.67

93. Denmeade S.R., Isaacs J.T. Engineering enzymatically activated «molecular grenades» for cancer. Oncotarget. 2012; 3 (7): 666–667. doi: 10.18632/oncotarget.562

94. Von Einem J.C., Guenther C., Volk H.D., Grütz G., Hirsch D., Salat C., Stoetzer O., Nelson P.J., Michl M., Modest D.P., Holch J.W., Angele M., Bruns C., Niess H., Heinemann V. Treatment of advanced gastrointestinal cancer with genetically modified autologous mesenchymal stem cells: Results from the phase 1/2 TREAT-ME-1 trial. Int. J. Cancer. 2019; 145 (6): 1538–1546. doi: 10.1002/ijc.32230

95. Albarenque S.M., Zwacka R.M., Mohr A. Both human and mouse mesenchymal stem cells promote breast cancer metastasis. Stem Cell Res. 2011; 7 (2): 163–171. doi: 10.1016/j.scr.2011.05.002

96. Kloner R.A. Stunned and hibernating myocardium: where are we nearly 4 decades later? J. Am. Heart Assoc. 2020; 9 (3): e015502. doi: 10.1161/JAHA.119.015502

97. Hocum Stone L.L., Swingen C., Wright C., Qi S.S., Rassette M., McFalls E.O., Kelly R.F. Recovery of hibernating myocardium using stem cell patch with coronary bypass surgery. J. Thorac. Cardiovasc. Surg. 2020; In Press. doi: 10.1016/j.jtcvs.2019.12.073

98. Vrtovec B., Poglajen G., Lezaic L., Sever M., Socan A., Domanovic D., Cernelc P., Torre-Amione G., Haddad F., Wu J.C. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation. 2013; 128 (11 Suppl 1): S42–S49. doi: 10.1161/CIRCULATIONAHA.112.000230

99. Schrepfer S., Deuse T., Reichenspurner H., Fischbein M.P., Robbins R.C., Pelletier M.P. Stem cell transplantation: the lung barrier. Transplant. Proc. 2007; 39 (2): 573–576. doi: 10.1016/j.transproceed.2006.12.019

100. Gholamrezanezhad A., Mirpour S., Bagheri M., Mohamadnejad M., Alimoghaddam K., Abdolahzadeh L., Saghari M., Malekzadeh R. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl. Med. Biol. 2011; 38 (7): 961–967. doi: 10.1016/j.nucmedbio.2011.03.008

101. Lee R.H., Pulin A.A., Seo M.J., Kota D.J., Ylostalo J., Larson B.L., Semprun-Prieto L., Delafontaine P., Prockop D.J. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009; 5 (1): 54–63. doi: 10.1016/j.stem.2009.05.003

102. Toma C., Wagner W.R., Bowry S., Schwartz A., Villanueva F. Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ. Res. 2009; 104 (3): 398–402. doi: 10.1161/CIRCRESAHA.108.187724

103. Zanetti A., Grata M., Etling E.B., Panday R., Villanueva F.S., Toma C. Suspension-expansion of bone marrow results in small mesenchymal stem cells exhibiting increased transpulmonary passage following intravenous administration. Tissue Eng. Part C. Methods. 2015; 21 (7): 683–692. doi: 10.1089/ten.TEC.2014.0344

104. Alimperti S., Lei P., Wen Y., Tian J., Campbell A.M., Andreadis S.T. Serum-free spheroid suspension culture maintains mesenchymal stem cell proliferation and differentiation potential. Biotechnol. Prog. 2014; 30 (4): 974–983. doi: 10.1002/btpr.1904

105. Fischer U.M., Harting M.T., Jimenez F., Monzon-Posadas W.O., Xue H., Savitz S.I., Laine G.A., Cox C.S.Jr. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009; 18 (5): 683–692. doi: 10.1089/scd.2008.0253

106. Porapakkham P., Porapakkham P., Zimmet H., Billah B., Krum H. B-type natriuretic peptide-guided heart failure therapy: a meta-analysis. Arch. Intern. Med. 2010; 170 (6): 507–514. doi: 10.1001/archinternmed.2010.35

107. Chow S.L., Maisel A.S., Anand I., Bozkurt B., de Boer R.A., Felker G.M., Fonarow G.C., Greenberg B., Januzzi J.L.Jr, Kiernan M.S., Liu P.P., Wang T.J., Yancy C.W., Zile M.R. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation. 2017; 135 (22): e1054e1091. doi: 10.1161/CIR.0000000000000490


Для цитирования:


Попандопуло А.Г., Турчин В.В., Солопов М.В., Буше В.В. Проблемы клинических испытаний эффективности клеточной терапии сегодня. Сибирский научный медицинский журнал. 2021;41(1):16-32. https://doi.org/10.18699/SSMJ20210102

For citation:


Popandopulo A.G., Turchyn V.V., Solopov M.V., Bushe V.V. Problems of clinical trials of cell therapy effectiveness today. Siberian Scientific Medical Journal. 2021;41(1):16-32. (In Russ.) https://doi.org/10.18699/SSMJ20210102

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