Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial
Authors: Stephen Westaby
Argirios Doumas
Polychronis Antonitsis
Kyriakos Anastasiadis
Sabena Sultan
Ajan Reginald
Martin John Evans
George Efthimiadis
Journal: Journal of Cardiovascular Translational Research (2016)
Discipline: CLINICAL MEDICINE
Keywords: Allogeneic; Coronary artery bypass grafting; Heart failure; Ischemic cardiomyopathy; Mesenchymal
Affiliations: Cardiothoracic Department, AHEPA University Hospital, S. Kyriakidi 1, 546 36, Thessaloniki, Greece., Cardiothoracic Department, AHEPA University Hospital, S. Kyriakidi 1, 546 36, Thessaloniki, Greece. ., The John Radcliffe Hospital, Oxford University Hospitals, Headington, Oxford, UK., Experimental Therapeutics, University of Oxford, Oxford, UK., Department of Nuclear Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece., First Cardiology Department, AHEPA University Hospital, Thessaloniki, Greece., School of Biosciences, Cardiff University, Wales, UK.

Abstract:  Heart failure is a life-limiting condition affecting over 40 million patients worldwide. Ischemic cardiomyopathy (ICM) is the most common cause. This study investigates in situ cardiac regeneration utilizing precision delivery of a novel mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ischemic cardiomyopathy (LVEF &lt; 40 %). The phase IIa safety study was designed to enroll 11 patients. Preoperative scintigraphy imaging (SPECT) was used to identify hibernating myocardium not suitable for conventional myocardial revascularization for iMP implantation. iMP cells were implanted intramyocardially in predefined viable peri-infarct areas that showed poor perfusion, which could not be grafted due to poor target vessel quality. Postoperatively, SPECT was then used to identify changes in scar area. Intramyocardial implantation of iMP cells with CABG was safe with preliminary evidence of efficacy of improved myocardial contractility and perfusion of nonrevascularized territories resulting in a significant reduction in left ventricular scar area at 12 months after treatment. Clinical improvement was associated with a significant improvement in quality of life at 6 months posttreatment in all patients. The results suggest the potential for in situ myocardial regeneration in ischemic heart failure by delivery of iMP cells. 

Retracted: No

PubPeer comments:
 The manuscript reports on the results of a trial that was undertaken at the AHEPA hospital, Thessaloniki, Greece, from 2012-2013. The trial involved injecting allogeneic u2018immunomodulatory progenitor cells (iMPs)u2019 into the myocardium of patients who were having coronary by-pass grafting. The u2018iMPsu2019 are described as a novel cell type that were **discovered and isolated in the UK by the company u2018Cell Therapy Ltdu2019** (now known as u2018Celixiru2019). The affiliations of three of the UK authors, Evans, Sultan and Reginald, are incorrect. At the time the manuscript was submitted, all three were Directors of Cell Therapy Ltd. Reginald has falsely listed his affiliation as u2018Experimental Therapeutics, University of Oxfordu2019: https: www.rdm.ox.ac.uk research experimental-therapeutics One of the groups listed on the above website is the u2018Antoniades Group: The Oxford Translational Cardiovascular Research Groupu2019. Although Prof Antoniades is a cardiologist of Greek origin, **he is not connected in any way to the AHEPA trial**. It is therefore curious why Reginald claimed to be affiliated with that particular Department. On 13th Nov 2015, one month after the manuscript was submitted, Cell Therapy Ltd sent a document to the European Patent Office, where it can be seen that the correct affiliation of Evans, Sultan and Reginald was The **Institute of Life Sciences, University of Swansea**: https: patentscope.wipo.int search en detail.jsf?docId=EP159726460 _cid=P21-K1XD8E-03210-3 This is a serious matter because this institute did not have approval from the Research Ethics Committee to prepare cells for therapeutic use. Moreover, the UK authors did not have access to Good Manufacturing Practice (GMP) facilities. The manuscript states that the donor cells were obtained from the **bone marrow of a healthy donor**. No information is given as to how this donor was solicited, nor whether ethical approval had been granted for this activity. Apart from these serious issues, data in the manuscript have been misrepresented. Table 1 presents flow cytometry data comparing expression levels of a variety of surface markers between u2018iMPsu2019 and bone marrow derived MSCs. The main purpose of these data are to show that iMPs are different from bone marrow-derived MSCs. However, analysis of a patent submitted by Cell Therapy Ltd shows that the u2018iMPsu2019 are actually MSCs derived from peripheral blood (PB-MSCs). The flow cytometry data from the u2018iMPsu2019 and PB-MSCs are identical. The patent is available here: https: patentscope.wipo.int search en detail.jsf?docId=EP159726460 tab=PCTDESCRIPTION _cid=P21-K1XD8E-03210-3 It is very concerning that the authors of this manuscript failed to mention that their u2018iMPu2019 flow cytometry data were actually obtained from cells that had been isolated from peripheral blood and not bone marrow. Of greater concern is that the PB-MSCs were not even obtained from healthy donors. The Companyu2019s PB-MSCs were isolated by a PhD student called Ina Laura Pieper, who undertook her PhD studies at the Companyu2019s base in Swansea University from 2010-2013. As indicated in the following manuscript that was published in 2017, the PB-MSCs were obtained from patients who had been admitted to the Morriston Hospital following a myocardial infarction (MI): https: onlinelibrary.wiley.com doi abs 10.1111 aor.12829 Pieper indicates in the manuscript that she was unable to isolate PB-MSCs from healthy volunteers, only the MI patients. Therefore, at the time that the AHEPA trial took place, the only PB-MSCs that Cell Therapy Limited could have analysed were those from the MI patients. It is very worrying that PB-MSCs derived from MI patients are presented in the manuscript as bone marrow-derived u2018iMPsu2019 obtained from a healthy donor. A crucial question is whether the PB-MSCs were also used in the trial. The Company are now planning to undertake a larger scale trial at the Royal Brompton Hospital, London, UK. **Will the patients participating in the new trial be fully informed of these questionable practices before giving their consent?** , 
 There seems to be a problem with the cardiac functional data in this paper. The left ventricular ejection fraction (LVEF) is important for assessing cardiac function. It can be calculated using the following calculation: LVEF (%) = left ventricular end diastolic volume (LVEDV) u2013 left ventricular end systolic volume (LVESV) x 100 LVEDV. If one calculates the baseline LVEF from the LVEDV (208.9) and the LVESV (106) given in Table 2, we get an LVEF of **49.3%** [i.e., (208.9-106) x100 208.9]. It is therefore difficult to understand why the value for LVEF in Table 2 is given as **37.2%**, as such a disparity could not be explained by rounding errors. Turning to Figure 2, we see that baseline LVEF is presented in what appears to be half a box-and-whisker plot, showing a median LVEF of 40% for the trial participants. If the median LVEF was 40%, this would mean that a proportion of the participants must have had an LVEF that was over 40%, which would be more consistent with the calculated average above of 49.3%. This is curious, because to be included in the trial, participants should have had an LVEF that was below or equal to 40%! Figure 2 suggests that LVEF improves from baseline to 1 month post op, and then stays relatively stable. However in Figure 3, one sees that the LVEDV was decreased compared with baseline at 1, 3, 6 and 12 months and LVESV changed little. So from these data, one would expect that LVEF would have decreased compared with baseline at each time point, and not increased as claimed. The authors gave 3 doses of iMP, but made no comment about a dose-response effect. This is very curious as one would normally expect the different doses to have been separated out. Otherwise, what is the point of the different doses? Could the authors please respond? , 
 Following on from the above comment. One would expect that after coronary artery bypass grafting (CABG), LVEF should improve. If the LVEDV and LVESV values in FIg 3 are correct, meaning that LVEF actually decreased, this would suggest that the cells were having a detrimental effect on the patients. , 
 Here I (Patricia Murray) am posting some letters that I have recently obtained under FOI from the European Medicines Authority (EMA). The first letter is from the EMA to the Greek regulators, asking them to invesitgate allegations of serious improprieties concering the conduct of the UK company Celixir (also known as Cell Therapy Ltd) in regard to 2 clinical trials they were involved with in Greece. The outcome of one of these trials is reported in this problematic manuscript. The second letter is the response from the Greek regulators, indicating that clinical trials that used Celixir s Heartcel (also known as iMPs) and Tendoncel therapies had been undertaken in Greece without the necessary regulatory and ethical approvals having been obtained. This manuscript should therefore be retracted. The Greek regulators state: *u201cAs a result of this serious GCP [Good Clinical Practice] and national legislation violation and further GCP deviations, the EOF Management Board imposed penalties to Celixir, Hospitals and Principal Investigators involved, as foreseen by national law.u201d* Letter 1:  Letter 2:  , 
 The following Editorial Note has now been added to his article: https: link.springer.com article 10.1007%2Fs12265-016-9686-0#change-history * The Editor-in-Chief is currently investigating this article (Anastasiadis et al. 2016) as concerns have been raised about the ethics and regulatory approvals related to the cells used in the research. Further editorial action will be taken as appropriate once the investigation into the concerns is complete and all parties have been given an opportunity to respond in full. * , 
 This article now has an Expression of Concern: https: link.springer.com article 10.1007%2Fs12265-020-10076-7 Some of the problems are mentioned but not the following ones: The flow cytometry data are misrpresented. The source of the data is a Celixir patent, and the cells analysed were MSCs from peripheral blood, not bone marrow-derived iMPs . The IRB approval that is mentioned was for the use of MSCs from peripheral blood, not iMPs from bone marrow. According to co-author Doumas, who is a radiologist, The SPECT scans were  trasferred to the trash soon after the article was published. It can therefore be concluded that everything about this paper is problematic. Hopefully ti will soon be retracted. It is particulary disappointing to see that the senior author, Martin Evans, appears to disagree with the Expression of Concern. ,