Một thử nghiệm lâm sàng giai đoạn Ib không ngẫu nhiên, không có đối chứng giả dược để nghiên cứu độ an toàn của tế bào nguồn gốc từ mô mỡ - phân đoạn mạch máu mô trong bệnh xơ phổi quảng tính
Tóm tắt
Y học tái sinh và đặc biệt là tế bào gốc trưởng thành đại diện cho một lựa chọn thay thế với nhiều ứng dụng điều trị thành công ở bệnh nhân bị bệnh phổi mạn tính, bao gồm xơ phổi vô căn (IPF). Tuy nhiên, sự thiếu hiểu biết về nguồn gốc và tiềm năng của tế bào gốc trung mô (MSCs) để biệt hóa thành nguyên bào sợi đã hạn chế việc sử dụng chúng trong điều trị căn bệnh tồi tệ này.
Để thực hiện điều này, chúng tôi đã tiến hành một thử nghiệm lâm sàng giai đoạn Ib không ngẫu nhiên để nghiên cứu độ an toàn của ba lần tiêm truyền nội soi phế quản tế bào nguồn gốc từ mỡ tự thân (ADSCs)-phân đoạn mạch máu mô (SVF) (0,5 triệu tế bào trên mỗi kg trọng lượng cơ thể cho mỗi lần tiêm) ở những bệnh nhân mắc IPF (n=14) có độ nặng bệnh từ nhẹ đến vừa (dung tích sống cưỡng bức – FVC >50% giá trị dự đoán và khả năng khuếch tán phổi đối với carbon monoxide - DLCO >35% giá trị dự đoán). Mục tiêu chính của chúng tôi là tỷ lệ xảy ra các sự kiện bất lợi phát sinh từ điều trị trong vòng 12 tháng. Những thay đổi về các thông số chức năng, khả năng tập thể dục và chất lượng cuộc sống tại các thời điểm thăm khám liên tiếp (cơ sở, 6 và 12 tháng sau lần truyền đầu tiên) được xem là mục tiêu thứ cấp mang tính khám phá.
Không có trường hợp nào ghi nhận các sự kiện bất lợi nghiêm trọng hoặc có ý nghĩa lâm sàng, bao gồm cả độc tính tức thì sau tiêm truyền cũng như hình thành mô ngoài vị trí lâu dài, ở tất cả các bệnh nhân. Việc giám sát an toàn chi tiết qua nhiều thời điểm cho thấy bệnh nhân được điều trị bằng tế bào không có sự suy giảm về cả các thông số chức năng và các chỉ số chất lượng cuộc sống.
Thử nghiệm lâm sàng đã đạt được mục tiêu chính của nó, cho thấy hồ sơ an toàn chấp nhận được của ADSCs-SVF được tiêm truyền nội soi phế quản. Những phát hiện của chúng tôi thúc đẩy kiến thức khoa học đang mở rộng nhanh chóng và cho thấy một hướng đi cho các thử nghiệm hiệu quả trong tương lai.
Từ khóa
Tài liệu tham khảo
Wuyts WA, Agostini C, Antoniou K, Bouros D, Chambers R, Cottin V: The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013, 41: 1207-1218. 10.1183/09031936.00073012.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK: An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011, 183: 788-824. 10.1164/rccm.2009-040GL.
Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D: Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011, 377: 1760-1769. 10.1016/S0140-6736(11)60405-4.
Bouros D: Pirfenidone for idiopathic pulmonary fibrosis. Lancet. 2011, 377: 1727-1729. 10.1016/S0140-6736(11)60546-1.
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG: Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011, 365: 1079-1087. 10.1056/NEJMoa1103690.
Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G: Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006, 174: 810-816. 10.1164/rccm.200602-163OC.
Raghu G: Improving the standard of care for patients with idiopathic pulmonary fibrosis requires participation in clinical trials. Chest. 2009, 136: 330-333. 10.1378/chest.09-0848.
Garcia-Gomez I, Elvira G, Zapata AG, Lamana ML, Ramirez M, Castro JG: Mesenchymal stem cells: biological properties and clinical applications. Expert Opin Biol Ther. 2010, 10: 1453-1468. 10.1517/14712598.2010.519333.
Gharaee-Kermani M, Gyetko MR, Hu B, Phan SH: New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy. Pharm Res. 2007, 24: 819-841. 10.1007/s11095-006-9216-x.
Kajstura J, Rota M, Hall SR, Hosoda T, D’Amario D, Sanada F: Evidence for human lung stem cells. N Engl J Med. 2011, 364: 1795-1806. 10.1056/NEJMoa1101324.
Moodley Y, Manuelpillai U, Weiss DJ: Cellular therapies for lung disease: a distant horizon. Respirology. 2011, 16: 223-237. 10.1111/j.1440-1843.2010.01914.x.
Tzouvelekis A, Antoniadis A, Bouros D: Stem cell therapy in pulmonary fibrosis. Curr Opin Pulm Med. 2011, 17: 368-373. 10.1097/MCP.0b013e328348744f.
Tzouvelekis A, Koliakos G, Ntolios P, Baira I, Bouros E, Oikonomou A: Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal. J Transl Med. 2011, 9: 182-10.1186/1479-5876-9-182.
Tzouvelekis A, Laurent G, Bouros D: Stem cell therapy in chronic obstructive pulmonary disease. Seeking the prometheus effect. Curr Drug Targets. 2013, 14: 246-252. 10.2174/1389450111314020009.
Weiss DJ, Bertoncello I, Borok Z, Kim C, Panoskaltsis-Mortari A, Reynolds S: Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc. 2011, 8: 223-272. 10.1513/pats.201012-071DW.
Toonkel RL, Hare JM, Matthay MA, Glassberg MK: Mesenchymal stem cells and idiopathic pulmonary fibrosis: potential for clinical testing. Am J Respir Crit Care Med. 2013, [Epub ahead of print]
Wang XX, Zhang FR, Shang YP, Zhu JH, Xie XD, Tao QM: Transplantation of autologous endothelial progenitor cells may be beneficial in patients with idiopathic pulmonary arterial hypertension: a pilot randomized controlled trial. J Am Coll Cardiol. 2007, 49: 1566-1571. 10.1016/j.jacc.2006.12.037.
Zeng C, Wang X, Hu X, Chen J, Wang L: Autologous endothelial progenitor cells transplantation for the therapy of primary pulmonary hypertension. Med Hypotheses. 2007, 68: 1292-1295. 10.1016/j.mehy.2006.09.062.
Tzouvelekis A, Ntolios P, Bouros D: Stem cell treatment for chronic lung diseases. Respiration. 2013, 85: 179-192. 10.1159/000346525.
Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL: Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013, 15: 641-648. 10.1016/j.jcyt.2013.02.006.
Astori G, Vignati F, Bardelli S, Tubio M, Gola M, Albertini V: “In vitro” and multicolor phenotypic characterization of cell subpopulations identified in fresh human adipose tissue stromal vascular fraction and in the derived mesenchymal stem cells. J Transl Med. 2007, 5: 55-10.1186/1479-5876-5-55.
Casteilla L, Planat-Benard V, Laharrague P, Cousin B: Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J Stem Cells. 2011, 3: 25-33. 10.4252/wjsc.v3.i4.25.
Casteilla L, Planat-Benard V, Bourin P, Laharrague P: Cousin B: [Use of adipose tissue in regenerative medicine]. Transfus Clin Biol. 2011, 18: 124-128. 10.1016/j.tracli.2011.01.008.
Casteilla L, Planat-Benard V, Dehez S, De BS, Barreau C, Andre M: Endothelial and cardiac regeneration from adipose tissues. Methods Mol Biol. 2011, 702: 269-287. 10.1007/978-1-61737-960-4_20.
Gimble JM, Guilak F, Bunnell BA: Clinical and preclinical translation of cell-based therapies using adipose tissue-derived cells. Stem Cell Res Ther. 2010, 1: 19-10.1186/scrt19.
Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H: Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002, 13: 4279-4295. 10.1091/mbc.E02-02-0105.
Mitchell JB, McIntosh K, Zvonic S, Garrett S, Floyd ZE, Kloster A: Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers. Stem Cells. 2006, 24: 376-385. 10.1634/stemcells.2005-0234.
Katsha AM, Ohkouchi S, Xin H, Kanehira M, Sun R, Nukiwa T: Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther. 2011, 19: 196-203. 10.1038/mt.2010.192.
Schweitzer KS, Johnstone BH, Garrison J, Rush NI, Cooper S, Traktuev DO: Adipose stem cell treatment in mice attenuates lung and systemic injury induced by cigarette smoking. Am J Respir Crit Care Med. 2011, 183: 215-225. 10.1164/rccm.201001-0126OC.
Sueblinvong V, Loi R, Eisenhauer PL, Bernstein IM, Suratt BT, Spees JL: Derivation of lung epithelium from human cord blood-derived mesenchymal stem cells. Am J Respir Crit Care Med. 2008, 177: 701-711. 10.1164/rccm.200706-859OC.
Zhen G, Liu H, Gu N, Zhang H, Xu Y, Zhang Z: Mesenchymal stem cells transplantation protects against rat pulmonary emphysema. Front Biosci. 2008, 13: 3415-3422.
Zhen G, Xue Z, Zhao J, Gu N, Tang Z, Xu Y: Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells. Cytotherapy. 2010, 12: 605-614. 10.3109/14653241003745888.
Aguilar S, Scotton CJ, McNulty K, Nye E, Stamp G, Laurent G: Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis. PLoS One. 2009, 4: e8013-10.1371/journal.pone.0008013.
Kumamoto M, Nishiwaki T, Matsuo N, Kimura H, Matsushima K: Minimally cultured bone marrow mesenchymal stem cells ameliorate fibrotic lung injury. Eur Respir J. 2009, 34: 740-748. 10.1183/09031936.00128508.
Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S: Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009, 175: 303-313. 10.2353/ajpath.2009.080629.
Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, Kaminski N: Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci USA. 2003, 100: 8407-8411. 10.1073/pnas.1432929100.
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J: Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005, 33: 145-152. 10.1165/rcmb.2004-0330OC.
Shigemura N, Okumura M, Mizuno S, Imanishi Y, Matsuyama A, Shiono H: Lung tissue engineering technique with adipose stromal cells improves surgical outcome for pulmonary emphysema. Am J Respir Crit Care Med. 2006, 174: 1199-1205. 10.1164/rccm.200603-406OC.
Shigemura N, Okumura M, Mizuno S, Imanishi Y, Nakamura T, Sawa Y: Autologous transplantation of adipose tissue-derived stromal cells ameliorates pulmonary emphysema. Am J Transplant. 2006, 6: 2592-2600. 10.1111/j.1600-6143.2006.01522.x.
Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP: 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: 2277-2286. 10.1016/j.jacc.2009.06.055.
Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY: Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012, 308: 2369-2379.
Traverse JH, Henry TD, Vaughan DE, Ellis SG, Pepine CJ, Willerson JT: LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction. Tex Heart Inst J. 2010, 37: 412-420.
Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX: Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA. 2011, 306: 2110-2119.
Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG: Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012, 308: 2380-2389.
Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T: Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2011, 6: 63-71.
Weiss DJ, Casaburi R, Flannery R, Leroux-Williams M, Tashkin DP: A placebo-controlled randomized trial of mesenchymal stem cells in chronic obstructive pulmonary disease. Chest. 2013, 143: 1590-1598.
Tzouvelekis A, Paspaliaris V, Koliakos G, Ntolios P, Oikonomou A, Froudarakis M: A prospective, non randomized, clinical trial to study the safety and efficacy of the endobronchial autologous infusion of adipose-derived mesenchymal stem cells (ADMSCs) in patients with idiopathic pulmonary fibrosis (IPF). Eur Respir J. 2011, 176 (3): Ref Type: Abstract
De Vos RJ, Weir A, Van Schie HT, Bierma-Zeinstra SM, Verhaar JA, Weinans H: Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA. 2010, 303: 144-149. 10.1001/jama.2009.1986.
Zurita M, Otero L, Aguayo C, Bonilla C, Ferreira E, Parajon A: Cell therapy for spinal cord repair: optimization of biologic scaffolds for survival and neural differentiation of human bone marrow stromal cells. Cytotherapy. 2010, 12: 522-537. 10.3109/14653241003615164.
Lin F, Josephs SF, Alexandrescu DT, Ramos F, Bogin V, Gammill V: Lasers, stem cells, and COPD. J Transl Med. 2010, 8: 16-10.1186/1479-5876-8-16.
Dominici M, Le BK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006, 8: 315-317. 10.1080/14653240600855905.
Werner J, Dragotakes SC, Fernandez-del CC, Rivera JA, Ou J, Rattner DW: Technetium-99m-labeled white blood cells: a new method to define the local and systemic role of leukocytes in acute experimental pancreatitis. Ann Surg. 1998, 227: 86-94. 10.1097/00000658-199801000-00013.
Folgiero V, Migliano E, Tedesco M, Iacovelli S, Bon G, Torre ML: Purification and characterization of adipose-derived stem cells from patients with lipoaspirate transplant. Cell Transplant. 2010, 19: 1225-1235. 10.3727/09638910X519265.
Krause A, Hohberg B, Heine F, John M, Burmester GR, Witt C: Cytokines derived from alveolar macrophages induce fever after bronchoscopy and bronchoalveolar lavage. Am J Respir Crit Care Med. 1997, 155: 1793-1797. 10.1164/ajrccm.155.5.9154894.
Perin EC, Silva GV, Henry TD, Cabreira-Hansen MG, Moore WH, Coulter SA: A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ischemic heart failure (FOCUS-HF). Am Heart J. 2011, 161: 1078-1087. 10.1016/j.ahj.2011.01.028.
Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX: Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012, 307: 1717-1726. 10.1001/jama.2012.418.
Wolf D, Wolf AM: Mesenchymal stem cells as cellular immunosuppressants. Lancet. 2008, 371: 1553-1554. 10.1016/S0140-6736(08)60666-2.
Zhao F, Zhang YF, Liu YG, Zhou JJ, Li ZK, Wu CG: Therapeutic effects of bone marrow-derived mesenchymal stem cells engraftment on bleomycin-induced lung injury in rats. Transplant Proc. 2008, 40: 1700-1705. 10.1016/j.transproceed.2008.01.080.
Alt EU, Senst C, Murthy SN, Slakey DP, Dupin CL, Chaffin AE: Aging alters tissue resident mesenchymal stem cell properties. Stem Cell Res. 2012, 8: 215-225. 10.1016/j.scr.2011.11.002.
Masato U, Akira N, Tatsuo N: Intravenous administration of adipose-derived stromal cells does not ameliorate bleomycin-induced lung injury in rats. Open J Regen Med. 2013, 2 (2): 39-45. 10.4236/ojrm.2013.22007.
Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A: Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation. 2003, 108: 863-868. 10.1161/01.CIR.0000084828.50310.6A.
Weiss DJ, Kolls JK, Ortiz LA, Panoskaltsis-Mortari A, Prockop DJ: Stem cells and cell therapies in lung biology and lung diseases. Proc Am Thorac Soc. 2008, 5: 637-667. 10.1513/pats.200804-037DW.
Moeller A, Gilpin SE, Ask K, Cox G, Cook D, Gauldie J: Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009, 179: 588-594. 10.1164/rccm.200810-1534OC.
Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM: Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol. 2007, 179: 2592-2599.
Feghali-Bostwick CA, Wilkes DS: Autoimmunity in idiopathic pulmonary fibrosis: are circulating autoantibodies pathogenic or epiphenomena?. Am J Respir Crit Care Med. 2011, 183: 692-693. 10.1164/rccm.201010-1727ED.
Kotsianidis I, Nakou E, Bouchliou I, Tzouvelekis A, Spanoudakis E, Steiropoulos P: Global impairment of CD4+CD25+FOXP3+ regulatory T cells in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2009, 179: 1121-1130. 10.1164/rccm.200812-1936OC.