Phase I clinical trial of cell therapy in patients with advanced chronic obstructive pulmonary disease: follow-up of up to 3 years

Talita Stessuk, Milton Artur Ruiz, Oswaldo Tadeu Greco, Aldemir Bilaqui, Maria José de Oliveira Ribeiro-Paes, João Tadeu Ribeiro-Paes, Talita Stessuk, Milton Artur Ruiz, Oswaldo Tadeu Greco, Aldemir Bilaqui, Maria José de Oliveira Ribeiro-Paes, João Tadeu Ribeiro-Paes

Abstract

Background: Chronic obstructive pulmonary disease is a major inflammatory disease of the airways and an enormous therapeutic challenge. Within the spectrum of chronic obstructive pulmonary disease, pulmonary emphysema is characterized by the destruction of the alveolar walls with an increase in the air spaces distal to the terminal bronchioles but without significant pulmonary fibrosis. Therapeutic options are limited and palliative since they are unable to promote morphological and functional regeneration of the alveolar tissue. In this context, new therapeutic approaches, such as cell therapy with adult stem cells, are being evaluated.

Objective: This article aims to describe the follow-up of up to 3 years after the beginning of a phase I clinical trial and discuss the spirometry parameters achieved by patients with advanced pulmonary emphysema treated with bone marrow mononuclear cells.

Methods: Four patients with advanced pulmonary emphysema were submitted to autologous infusion of bone marrow mononuclear cells. Follow-ups were performed by spirometry up to 3 years after the procedure.

Results: The results showed that autologous cell therapy in patients having chronic obstructive pulmonary disease is a safe procedure and free of adverse effects. There was an improvement in laboratory parameters (spirometry) and a slowing down in the process of pathological degeneration. Also, patients reported improvements in the clinical condition and quality of life.

Conclusions: Despite being in the initial stage and in spite of the small sample, the results of the clinical protocol of cell therapy in advanced pulmonary emphysema as proposed in this study, open new therapeutic perspectives in chronic obstructive pulmonary disease. It is worth emphasizing that this study corresponds to the first study in the literature that reports a change in the natural history of pulmonary emphysema after the use of cell therapy with a pool of bone marrow mononuclear cells.

Keywords: Cell transplantation; Clinical trial, phase I; Pulmonary disease, chronic obstructive; Pulmonary emphysema; Spirometry; Stem cells.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interest

Figures

Figure 1
Figure 1
Spirometric values achieved by Patient 2; A) Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC) and vital capacity (VC); B) Percentages predicted for FEV1, FVC and the FEV1/FVC ratio; pre- and post-bronchodilator values
Figure 2
Figure 2
Spirometric values achieved by Patient 3; A) Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC) and vital capacity (VC); B) Percentages predicted for FEV1, FVC and the FEV1/FVC ratio; pre- and post-bronchodilator values
Figure 3
Figure 3
Spirometric values achieved by Patient 4; A) Forced expiratory volume in 1 second (FEV1), Forced vital capacity (FVC) and vital capacity (VC); B) Percentages predicted for FEV1, FVC and the FEV1/FVC ratio; pre- and post-bronchodilator values

References

    1. Global Initiative for Chronic Obstructive Lung Disease GOLD Global Strategy for Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease [Internet] [cited 2013 June 02]. Available from: .
    1. II Consenso Brasileiro sobre Doença Pulmonar Obstrutiva Crônica (DPOC) J Bras Pneumol. 2004;30(Supl 5):S1–S42.
    1. Mannino DM. The natural history of chronic obstructive pulmonary disease. Pneumonol Alergol Pol. 2011;79(2):139–143.
    1. Faria CA de, las Heras Kozma R de, Stessuk T, Ribeiro-Paes JT. Experimental basis and new insights for cell therapy in Chronic Obstructive Pulmonary Disease. Stem Cell Rev. 2012;8(4):1236–1244.
    1. Ribeiro-Paes JT, Stessuk T, Heras Kozma R de. Cell therapy in Chronic Obstructive Pulmonary Disease: state of the art and perspectives. In: Kian-Chung, editor. Chronic Obstructive Pulmonary Disease - Current Concepts and Practice [Internet] Singapore: Intech; 2012. [cited 2012 mar 2]. Available from: .
    1. Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(6):1304–1309.
    1. Barnes PJ. New concepts in chronic obstructive pulmonary disease. Annu Rev Med. 2003;54:113–129.
    1. Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Alves-de-Moraes LB, Faria CA, et al. Terapia celular em doenças pulmonares: existem perspectivas? Rev Bras Hematol Hemoter. 2009;31(Supl.1):140–148.
    1. Mannino DM, Buist AS. Global burden of COPD: risk factors, prevalence, and future trends. Lancet. 2007;370(9589):765–773.
    1. Lee J, Sandford A, Man P, Sin DD. Is the aging process accelerated in chronic obstructive pulmonary disease. Curr Opin Pulm Med. 2011;17(2):90–97.
    1. Seixas S, Garcia O, Trovoada MJ, Santos MT, Amorim A, Rocha J. Patterns of haplotype diversity within the serpin gene cluster at 14q32.1: insights into the natural history of the alpha1-antitrypsin polymorphism. Hum Genet. 2001;108(1):20–30.
    1. World Health Organization . Third General Meeting. Istanbul: Geneva: WHO; May 30-31, 2008. 2008. [cited 2010 May 21]. Global alliance against chronic respiratory diseases (GARD). General Meeting [Internet] Available from:
    1. Murray CJ, Lopez AD. Mortality by cause for eight regions of the world: Global Burden of Disease Study. Lancet. 1997;349(9061):1269–1276. Comment in: Lancet. 1997;349(9061):1263; Lancet. 1997;350(9071):142; Lancet. 1997; 350(9071):144; Lancet. 1997;350(9071):141-2; author reply 144-5.
    1. Raghavan N, Webb K, Amornputtisathaporn N, O'Donnell DE. Recent advances in pharmacotherapy for dyspnea in COPD. Curr Opin Pharmacol. 2011;11(3):204–210.
    1. Yamada M, Kubo H, Kobayashi S, Ishizawa K, Numasaki M, Ueda S, et al. Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol. 2004;172(2):1266–1272.
    1. Ishizawa K, Kubo H, Yamada M, Kobayashi S, Numasaki M, Ueda S, et al. Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema. FEBS Lett. 2004;556(1-3):249–252.
    1. Kuang PP, Lucey E, Rishikof DC, Humphries DE, Bronsnick D, Goldstein RH. Engraftment of neonatal lung fibroblasts into the normal and elastase-injured lung. Am J Respir Cell Mol Biol. 2005;33(4):371–377.
    1. Murakami S, Nagaya N, Itoh T, Iwase T, Fujisato T, Nishioka K, et al. Adrenomedullin regenerates alveoli and vasculature in elastaseinduced pulmonary emphysema in mice. Am J Respir Crit Care Med. 2005;172(5):581–589.
    1. Adachi Y, Oyaizu H, Taketani S, Minamino K, Yamaguchi K, Shultz LD, et al. Treatment and transfer of emphysema by a new bone marrow transplantation method from normal mice to Tsk mice and vice versa. Stem Cells. 2006;24(9):2071–2077.
    1. Agostini C. Stem cell therapy for chronic lung diseases: hope and reality. Respir Med. 2010;104(Suppl 1):S86–S91.
    1. Jones CP, Rankin SM. Bone marrow-derived stem cells and respiratory disease. Chest. 2011;140(1):205–211.
    1. Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development. 2001;128(24):5181–5188.
    1. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005;33(2):145–152.
    1. Lama VN, Smith L, Badri L, Flint A, Andrei AC, Murray S, et al. Evidence for tissue-resident mesenchymal stem cells in human adult lung from studies of transplanted allografts. J Clin Invest. 2007;117(4):989–996.
    1. Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP. Stem cell transplantation: the lung barrier. Transplant Proc. 2007;39(2):573–576.
    1. Ribeiro-Paes JT, Bilaqui A, Greco OT, Ruiz MA, Marcelino MY, Stessuk T, et al. Unicentric study of cell therapy in chronic obstructive pulmonary disease/pulmonary emphysema. Int J Chron Obstruct Pulmon Dis. 2011;6:63–71.
    1. Tzouvelekis A, Ntolios P, Bouros D. Stem cell treatment for chronic lung diseases. Respiration. 2013;85(3):179–192.
    1. Fabbri LM. Spirometric inclusion criteria of COPD patients in randomized clinical trials. Respir Med. 2012;106(6):912–913. Comment on: Respir Med. 2012;106(1):84-90.
    1. Liang BM, Lam DC, Feng YL. Clinical applications of lung function tests: a revisit. Respirology. 2012;17(4):611–619.
    1. Weiss DJ, Casaburi R, Flannery R, LeRoux-Williams M, Tashkin DP. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590–1598. Comment in: Chest. 2013;143(6):1525-7.
    1. Machado CV, Telles PD, Nascimento IL. Immunological characteristics of mesenchymal stem cells. Rev Bras Hematol Hemoter. 2013;35(1):62–67.
    1. Longhini-Dos-Santos N, Barbosa-de-Oliveira VA, Kozma RH, Faria CA, Stessuk T, Frei F, et al. Cell therapy with bone marrow mononuclear cells in elastase-induced pulmonary emphysema. Stem Cell Rev. 2013;9(2):210–218.
    1. Katsha AM, Ohkouchi S, Xin H, Kanehira M, Sun R, Nukiwa T, et al. Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. Mol Ther. 2011;19(1):196–203.
    1. Yuhgetsu H, Ohno Y, Funaguchi N, Asai T, Sawada M, Takemura G, et al. Beneficial effects of autologous bone marrow mononuclear cell transplantation against elastase-induced emphysema in rabbits. Exp Lung Res. 2006;32(9):413–426.
    1. Engström G, Lind P, Hedblad B, Wollmer P, Stavenow L, Janzon L, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation. 2002;106(20):2555–2560.

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