Idiopathic Pulmonary Fibrosis 2

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A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis

Text of Idiopathic Pulmonary Fibrosis 2

  • RESEARCH Open Access

    A prospective, non-randomized, noIb clinical trial to study

    6 and 12 months after first infusion) were exploratory secondary end-points.

    Tzouvelekis et al. Journal of Translational Medicine 2013, 11:171http://www.translational-medicine.com/content/11/1/171Democritus University of Thrace, Alexandroupolis 68100, GreeceFull list of author information is available at the end of the articleResults: No cases of serious or clinically meaningful adverse events including short-term infusional toxicities aswell as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring throughseveral time-points indicated that cell-treated patients did not deteriorate in both functional parameters andindicators of quality of life.

    Conclusions: The clinical trial met its primary objective demonstrating an acceptable safety profile ofendobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientificknowledge and indicate a way towards future efficacy trials.

    Keywords: Adipose derived stromal cells, Mesenchymal stem cells, Idiopathic pulmonary fibrosis, Safety,Clinical trial, Stromal vascular fraction

    * Correspondence: bouros@med.duth.gr1Department of Pneumonology, Medical School, Democritus University ofThrace, Alexandroupolis, Greece10Department of Pneumonology, University Hospital of Alexandroupolis,the safety of the adipose derived stromalcells-stromal vascular fraction in idiopathicpulmonary fibrosisArgyris Tzouvelekis1, Vassilis Paspaliaris2, George Koliakos3,4, Paschalis Ntolios1, Evangelos Bouros5,Anastasia Oikonomou6, Athanassios Zissimopoulos7, Nikolaos Boussios7, Brian Dardzinski3,4, Dimitrios Gritzalis8,Antonis Antoniadis9, Marios Froudarakis1, George Kolios5 and Demosthenes Bouros1,10*

    Abstract

    Introduction: Regenerative medicine and particular adult stem cells represent an alternative option with severalfruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonaryfibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells(MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease.

    Patients and methods: To this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety ofthree endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF)(0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate diseaseseverity (forced vital capacity FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35%of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline,placebo-controlled, phase 2013 Tzouvelekis et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of theCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.

  • Tzouvelekis et al. Journal of Translational Medicine 2013, 11:171 Page 2 of 13http://www.translational-medicine.com/content/11/1/171IntroductionIdiopathic pulmonary fibrosis (IPF) is a devastating,fibroproliferative chronic lung disorder with complexand yet unknown disease biology. As a result, there is nocurrent standard of care for patients with IPF since boththe disease and the effort to treat it are moving targets[1,2]. The specific pathogenetic pathway, type of cells orcellular products that should be targeted are under de-bate. This lack of information has led physicians to applya more oncologic approach with the administration ofdrug regimens that inhibit multiple pathogenetic path-ways, including pirfenidone [3,4] and tyrosine kinase in-hibitors [5], with potential important side-effects. Despiteextensive research efforts and large multicenter clinicaltrials, IPF continues to exercise a heavy human, financialand societal toll on its victims, their loved ones and theircommunities in which they work and live. With a grad-ually increasing worldwide [6] incidence and in view ofthe current disappointing status of available pharmaceut-ical agents the need for developing new treatments for IPFthat are safe, effective and tolerable is now more challen-ging than ever [7].Regenerative medicine and particular adult stem cells

    represent one such alternative option with several fruitfultherapeutic applications in patients suffering from chroniclung diseases including IPF [8-19]. The past 5 years inves-tigations of the therapeutic potential of adult stem cellsand particular mesenchymal stem cells (MSCs) in experi-mental models of chronic lung diseases have expandedrapidly [15]. MSCs are stromal cells that can be readilyharvested from numerous tissues, including bone marrow(BM), stromal vascular fraction (SVF) of the adipose tissueand cord blood [8,12,15]. Based on the recently publishedstatement of International Federation for Adipose Thera-peutics and Science (IFATS) and the International Societyfor Cellular Therapy (ISCT) [20], SVF is a supportivestroma lying within adipose tissue, which represents anabundant and easily accessible source of a heterogeneouscell population including hematopoietic and endothelialprecursors as well as erythrocytes, fibroblasts, lympho-cytes, monocyte/macrophages and pericytes [20-27]. How-ever, the most important cell subpopulation of SVF isadipose-derived stromal cells (ADSCs) that seem to repre-sent approximately 20% of initially isolated SVF cells.When SVF cells are seeded into culture they can be fur-ther purified from hematopoietic cellular componentsallowing increased expression of stromal markers (CD29,73, 13, 90, 105 greater than 80% of cells) and progressiveloss of stem cell associated (CD34) and hematopoietic(CD45) markers, a phenotypic profile resembling that ofBM-MSCs.Based on their unique pleiotropic paracrine properties[28-32], BM or umbilical cord MSCs, and adipose derivedstromal cells - stromal vascular fraction (ADSCs-SVF)have been demonstrated to exert beneficial therapeuticeffects in the experimental model of lung fibrosis [33-37]and emphysema [29,38,39], respectively.On the contrary with pulmonary and critical care

    medicine, the use of stem cell therapy is now beingestablished to patients suffering from complicationsfollowing acute myocardial infarction [40-45]. Althoughefficacy results arising from these studies seem ratherconfusing and conflicting, all of them were characterizedby encouraging safety data. The latter studies offeredpivotal clinical insights and accidentally in one of themauthors came up with an exploratory finding as theyreported lung function improvement in the majority ofpatients [40]. This observation captured interest of chestphysicians and triggered the launch of two clinical trialsassessing the safety and efficacy of intravenous infusionof allogeneic BM-MSCs in patients with moderate andsevere COPD. Encouragingly both studies reported anacceptable safety profile while none of them finally metefficacy objectives [46,47]. However, there is significantlack of knowledge regarding the exact fate of these cellswithin a fibrotic microenvironment, evidence that haslimited their widespread clinical applicability.To provide useful clinical insights that will help us to

    overcome major safety and ethical concerns acceleratingthe application status of stem cell therapy in IPF, weconducted a phase Ib non randomized, no placebo con-trolled, clinical trial to primarily study the safety profileof the endobronchial infusion of ADSCs-SVF, in patientswith IPF of mild to moderate disease severity as assessedby functional status. Parameters related to functionalprofile, including forced vital capacity (FVC), diffusionlung capacity for carbon dioxide (DLCO), exercise capacity(6-minute walking test-MWT) and quality of life (SaintGeorges Research Questionnaire-SGRQ were investigatedas secondary exploratory end-points. Some of the resultsof these studies have been previously reported in the formof an abstract [48].

    Patients and methodsTrial designThis study was a phase Ib, non-randomized, noplacebo-controlled, unicentric clinical trial, conductedat the Department of Pneumonology, Medical School,Democritus University of Thrace and University Hospitalof Alexandroupolis, Greece. Our study followed an alreadypublished protocol (inclusion, exclusion criteria, primaryand secondary end-points) with slight modifications[13]. Our primary aim was to investigate the safety pro-file of autologous endobronchially administered autolo-gous ADSCs-SVF in patients suffering from IPF basedon the recently published diagnostic criteria of ATS/

    ERS (2011) [2], of mild to moderate disease severity asestimated by functional parameters including FVC

  • >50% and DLCO >35% of the predicted normal values.Our exploratory secondary goals were to assess efficacyof stem cell infusion based on functional, exercise cap-acity and quality of life criteria analyzed below. BetweenJune of 2010 and September of 2011, a total of 20 pa-tients were screened for enrolment in the study. Amongthem, 5 were excluded due to DLCO
  • Tzouvelekis et al. Journal of Translational Medicine 2013, 11:171 Page 4 of 13http://www.translational-medicine.com/content/11/1/171a lyophilized molecule that helps 99mTc to enter withinthe cell membranes) according to a modified protocol[53]. Retention of radiolabeled cells (99mTc-HMPAO)within both lungs was estimated with computerizedimage analysis by drawing regions of interest and calcu-lating the average counts/pixels (average count). Details