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

Argyris Tzouvelekis, Vassilis Paspaliaris, George Koliakos, Paschalis Ntolios, Evangelos Bouros, Anastasia Oikonomou, Athanassios Zissimopoulos, Nikolaos Boussios, Brian Dardzinski, Dimitrios Gritzalis, Antonis Antoniadis, Marios Froudarakis, George Kolios, Demosthenes Bouros, Argyris Tzouvelekis, Vassilis Paspaliaris, George Koliakos, Paschalis Ntolios, Evangelos Bouros, Anastasia Oikonomou, Athanassios Zissimopoulos, Nikolaos Boussios, Brian Dardzinski, Dimitrios Gritzalis, Antonis Antoniadis, Marios Froudarakis, George Kolios, Demosthenes Bouros

Abstract

Introduction: Regenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (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 of three 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 disease severity (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 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points.

Results: No cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life.

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

Figures

Figure 1
Figure 1
Schematic representation of the study protocol synopsis.
Figure 2
Figure 2
Exploratory efficacy end-points before and after endobronchial infusion of adipose derived stromal cells-stromal vascular fraction (ADSCs-SVF). A. Forced vital capacity (FVC)% pred. over time for each subject. Each line represents measurements made in a single subject. A time point 0 months indicates when first endobronchial infusion of the ADSCs-SVF was performed. As depicted, there were no statistically significant alterations between baseline and after 6 and 12 months following 1st endobronchial infusion. A time point −3 months indicates period of time prior treatment initiation. B. Diffusion lung capacity for carbon monoxide (DLCO)% pred. over time for each subject. Each line represents measurements made in a single subject. As depicted, there were no statistically significant alterations between baseline and after 6 and 12 months following 1st endobronchial infusion. A time point 0 months indicates when first endobronchial infusion of ADSCs-SVF was performed. A time point −3 months indicates period of time prior treatment initiation. C. 6-minute walking distance (6MWD) over time. As depicted, there were no statistically significant alterations between baseline and after 6 and 12 months following 1st endobronchial infusion of the ADSCs-SVF. A time point −3 months indicates period of time prior treatment initiation. D. Saint George’s Research Questionnaire (SGRQ) score over time. A time point 0 months indicates when first endobronchial infusion of the ADSCs-SVF was performed. As depicted, there was a statistically significant decline between baseline (0 months) and after 6 and 12 months following 1st endobronchial infusion. *p<0.05.
Figure 3
Figure 3
99mTc lung scintigraphy at different time points (30 min, 90 min and 24 hours) after endobronchial infusion of the adipose derived stromal cells-stromal vascular fraction (ADSCs-SVF) in two representative subjects (right and left panel, A, B and C, respectively). Retention of radiolabeled cells (99mTc-HMPAO) within both lungs was estimated with computerized image analysis by drawing regions of interest (roi) and calculating the average counts/pixels (average count). As depicted, signal intensity in both patients (right and left panel), although exhibited an expected decline through serial time-points (30 min vs. 90 min vs. 24 hours), nevertheless was present even 24 hours after the infusion. The latter evidence indicates the presence of ADSCs-SVF since free technetium (99mTcO4) has a half-time life equal to 6 hours and therefore it was impossible to produce signal 24 hours after the infusion.

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