The present study is reporting long-term safety and efficacy data for the first in man randomized, double-blinded placebo-controlled study using VEGF-A165 stimulated culture expanded ASCs for patients with refractory angina.
The bicycle exercise performance decreased significantly in the placebo group but was unchanged in the ASC group except for the performance measured in METs at 3 years follow-up.
Cardiac symptoms measured as CCS class and the numbers of weekly angina attacks were significantly reduced during the 3 years of follow-up time for the patients treated with ASCs while there were no changes for the patients receiving saline injections. However, use of short-term nitroglycerin was un-changed in both groups.
For patients in both groups, significant improved quality-of-life, angina stability, angina frequency and physical limitation score was observed.
Chronic ischemic heart disease is a progressive disease. During the follow-up period of 3 years, 13 patients were admitted due to acute myocardial infarction and 26 due to angina worsening. The decrease in bicycle performance in the placebo group illustrates the progressive nature of coronary artery disease.
Interestingly, during the first 6 months follow-up period, significant improvement in heart symptoms of all patients was seen. However, the present long-term data demonstrated that patients allocated into the saline group returned to baseline cardiac symptoms but for patients in the ASC group, the heart symptoms remained decreased during the entire follow-up period. Along with this, the number of weekly angina attacks was only reduced in the ASC group. It can be speculated whether this effect over time in reduced cardiac symptoms would have been seen if only growth factors were injected. However, injection of growth factors may result in rapid dilution while ASCs are bigger in size and may stay in the injected tissue for a time period. Moreover, ASCs may secrete a cocktail of growth factors in a highly complex manner to promote angiogenesis. Nevertheless, for the patients it is highly important that any type of treatment results in decreased morbidity and mortality.
Previous published studies using exercise test as an outcome measure, show similar change in exercise capacity after CD34+ injections in patients with chronic ischemic heart disease and refractory angina [17,18,19]. In these studies, the patients received a standardized dose of cells. In the present study, the patients received the total amount of cells reached after two cell culture expansion passages and thus there were a patient-to-patient variation in the number of cells delivered.
Intra-myocardial injection of freshly harvested adipose-derived cells have been used in patients with refractory angina, which showed that exercise capacity measured as METs in the cell group remained stable while there was a decrease in METs in the placebo group . It is the same tendency as in our study.
Another study also using freshly harvested autologous adipose derived cells injected intramyocardially in patients with ischemic heart failure showed increased maximum oxygen consumption on exercise treadmill in patients receiving cells but did not differed significantly from the placebo group .
Another small study delivering freshly harvested adipose-derived cells intracoronary in patients with ST-elevations myocardial infarction showed a trend towards improved LVEF .
Previously at our center, we have conducted studies using autologous bone marrow derived mesenchymal stromal cells for patients with chronic ischemic heart disease with and without heart failure [20,21,22]. These studies have demonstrated improvement in patients self-reported health, increase in LVEF, decreased left ventricular end-systolic volume and reduced amount of scar tissue.
It has been increasingly clear for many research groups, that the expansion of autologous cells in flasks makes it very difficult to deliver a standardized stem cell treatment. New cell culture methods using bioreactor systems to reach a standardized cell count for allogeneic treatments are now available for clinical use . These systems have been used in a phase I trial, to produce an allogeneic cell product (CSCC_ASC) comparable to the one used in this trial as autologous product, for treatment in 10 patients with ischemic heart failure . The aim was to investigate the safety of intra-myocardial injections of 100 million ASCs from healthy donors. No treatment-related side effects were observed.
Furthermore, CSCC_ASC is being tested in a Danish and European multicentre double-blinded placebo-controlled trial for treatment of patients with ischemic heart failure (EudraCT: 2015-001560-19 and EudraCT: 2015-002929-19, respectively) [25, 26].
Moreover, a single-centre study initiated January 2019 is investigating CSCC_ASC in patients with non-ischemic heart failure (EudraCT: 2018-002538-19).
In this study, the total amount of ASCs reached were injected into the patients allocated to the active therapy group, while the adipose tissue obtained from some of the patients in the placebo group, were used for characterization of ASCs . Gene expression levels by quantitative real-time PCR analysis of ASCs showed that transcription of endothelial markers FOXF1, vWF, and VEGFR1 were up-regulated. By flow cytometry, we found the characteristic mesenchymal stem cell markers CD13, CD73, CD90, and CD105 on ASCs and they were lacking HLA-DR, CD19, and CD14.
So, the accumulated experience from clinical stem cell trials, the established safety and efficacy data has led this field to move from autologous to allogeneic therapy, reducing the logistical obstacles meet in previous studies. Furthermore, this field moves on to give a standardized amount of cell therapy safely and equally to all patients. However, as it is known from traditional pharmaceutical therapies, mostly repeated treatment is used. It may be of interest to investigate the role of cell therapy with two treatments within a short period.
The obvious benefit of cell therapy may be that it has the potential to regenerate the ischemic myocardium compared to conventional medical and interventional therapies. However, we did not have long term imaging modalities to detect changes in myocardial perfusion . Moreover, in a selected group of patients the yield of cells and the effect of therapy may be higher . Even though, this study is a randomized clinical trial, there were only male in the placebo group and a trend towards significant difference between the two groups for hypertension and previous coronary artery bypass grafting. Thus, these factors could potential be confounders.
Even though, the primary end-point did not differ between the two groups at 6 months follow-up, there was at 6 months follow-up a significant increase in bicycle exercise capacity in the ASC group, which was not the case for patients in the placebo group.
Probably, a larger amount of patients were needed in this study to detect a significant difference between groups for the primary end point. However, reduced cardiac symptoms are essential for the patient’s quality of life, which was seen only for the patients in the ASC group in this long-term follow-up period.