Clinical trials of cell therapy for heart failure: recent results warrant continued research

INTRODUCTION

The status of cell therapy for heart failure has been extensively reviewed The purpose of this article is to summarize the trials of cell therapy in heart failure that have been published (or presented) in the past 18 months. 

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RECENT TRIALS OF CELL THERAPY IN HEART FAILURE ALLSTAR

ALLSTAR was a Phase II, randomized, double-blind, placebo-controlled, multicenter trial of cardiosphere-derived cells (CDCs) in patients who had suffered a myocardial infarction (MI) in the previous 1–12 months and had left ventricle (LV) dysfunction [2,3]. A total of 142 patients were randomized 2:1 to intracoronary infusion of 25 × 106 allogeneic CDCs or placebo, at an average of 4.6 months after MI. The primary endpoint was the size of the LV scar, measured by MRI, at 12 months after treatment. However, the sponsor stopped the trial early, after an interim analysis of the data obtained at 6 months of follow-up revealed futility to meet the primary endpoint; thus, results at 12 months are not available. The results obtained at 6 months showed that there was no difference in scar size between the CDC-treated and the placebo groups. There was also no significant difference in left ventricular ejection fraction (LVEF), although there was a small decrease in left ventricular end-diastolic volume (–4.5 ml), left ventricular end-systolic volume (LVESV) (–4.8 ml), and plasma levels of NT-proBNP (–303 pg/ml) in the CDC-treated group vs.placebo.Thus, ALLSTAR failed to reproduce the results of CADUCEUS, an earlier Phase I, single-center, open-label, Phase I study of 31 patients [4].

Interpretation of ALLSTAR is problematic for many reasons. The primary endpoint was not assessed because the study was stopped before the follow-up was completed. The decision to report results at 6 months instead of 12 months was made post hoc. The study population was quite heterogeneous because it included patients with a recent MI (1–2 months) and with an old MI (>6 months), and patients with both ST-elevation myocardial infarction and non-ST-elevation myocardial infarction. The average baseline LVEF was 40%, indicating that the degree of LV dysfunction was relatively minor. Important clinical data, including medications, presence of multivessel disease, comorbidities, diastolic dysfunction, and BMI, were not collected consistently. There was no information on the type of MI in 58 of the 142 patients. Taken together, these issues make it difficult to interpret the results of ALLSTAR [2,3] in a meaningful manner.

MSC-HF

Some of the most encouraging results in the field of cell therapy for heart failure have come from MSC-HF, a Phase II, randomized, double-blind, placebo-controlled study of autologous bone marrow mes-enchymal stromal cells (BM-MSCs) in ischemic heart failure [5▪▪,6]. The initial 6-month results were published a few years ago [6], and the final 4-year data in 2020 [5▪▪]. In this study, 60 patients with ischemic heart failure (NYHA class II–III; LVEF < 45% by MRI) were randomized 2: 1 to trans-endocardial injection of autologous BM-MSCs or placebo and followed for 12 months; in addition, data on hospitalizations and survival were obtained at 4 years. The primary endpoint was the change in LVESV at 12 months. This endpoint was met: the trial showed a highly significant reduction in LVESV of 17 ml (P< 0.0002) at 12 months. In addition, MSC-treated patients had a highly significant improvement in LVEF (+6.2 units; P < 0.0001), myocardial mass (+9.8 g; P = 0.09), and quality of life at 12 months (Fig. 1). The data collected at 4 years of follow-up showed a significant reduction in the hospitalizations for angina in the MSC group, although there were no significant differences in overall hospitalization or survival [5▪▪].

F1FIGURE 1: Effect of autologous bone marrow mesenchymal stromal cells on left ventricle end-systolic volume and ejection fraction in the MSC-HF trial. Reproduced with permission [5▪▪].

Several features of MSC-HF should be underscored. First, this trial met its primary endpoint, thereby refuting misleading statements in the literature that no cell therapy study has met its primary endpoint in cardiac disease [7]. Second, the differences between MSC-treated and placebo patients were highly significant. Third, the effects of a single injection of MSCs were long-lasting, being observed for at least 12 months and, in the case of hospitaliza-tion for angina, for at least 4 years after treatment. Finally, these impressive results were obtained despite the fact that this trial used autologous MSCs, which are now obsolete, since virtually all current trials of cell therapy use allogeneic cells Since allogeneic cell products are obtained from young, healthy donors, it seems very likely that they will be more effective than autologous products obtained from older patients with significant comorbidities--a concept supported by published clinical trials, such as POSEIDON [8] and POSEIDON-DCM [9]. If this is the case, the results of MSC-HF would be expected to be even more robust with the use of allogeneic MSCs.

Another interesting aspect of MSC-HF is that patients were given different amounts of MSCs, depending on the amount and quality of the bone marrow that was harvested in each of them. This heterogeneity provided an opportunity to examine the dose–response relationship between cell number and outcome, which can rarely be done in clinical trials since the dose of cells is usually fixed. MSC-HF found that the greatest benefits (reduction in LVESV and LVEF) were observed in the upper tertile of cell doses (>83 × 106 cells) and that the changes observed in this tertile were significantly greater than those observed in the lower tertile (<43 × 106 cells). These data suggest a positive relationship between the number of MSCs injected and the clinical outcome; a conclusion that is also supported by the results of the TRIDENT study [10]. Based on the results of MSC-HF and TRIDENT, it appears that transendocardial doses of BM-MSCs should be in the 100–150 × 106 range.

CONCERT-HF

CONCERT-HF was a Phase II, randomized, placebo-controlled, double-blind, multicenter studyof autol-ogous BM-MSCs, c-kit-positive cardiac cells (CPCs), or both, in patients with ischemic heart failure [11,12▪▪]. The study was conducted by the Cardiovascular Cell Therapy Research Network (CCTRN), a network that was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and that the NHLBI decided not to renew 2 years ago. CON-CERT-HF was arguably the most rigorous clinical trial of cell therapy for heart failure conducted heretofore. The oversight of this study was extraordinarily rigorous, including a Protocol Review Committee, a Data Safety and Monitoring Board, a Steering Committee, a Protocol Development Committee, the local Institutional Review Boards, and the Food and Drug Administration. Developing the final protocol required several years of discussions and review of data and protocols by the various bodies.

CONCERT-HF started with a pilot, open-label study that was mandated by the FDA to assess feasibility and safety [11,12▪▪]. It included 18 patients who were randomized to either the combination of autologous MSCs and CPCs or standard of care, and were followed for 3 months. The main study consisted of 125 patients with ischemic heart failure enrolled at seven CCTRN centers from November 2016 to October 2018. The average LVEF was 29%, the average scar size was 19.4% of LV mass, and most patients (80%) were in NYHA class II, with 15% in class III. Patients were randomized 1: 1: 1: 1 to the combination of MSCs and CPCs, MSCs alone, CPCs alone, or placebo (target doses, 150 × 106 MSCs and 5 × 106 CPCs). All patients underwent bone marrow aspiration and right heart catheteriza-tion. To limit adverse events, endomyocardial biopsy was performed only in patients from whom CPCs were grown (MSCs + CPCs and CPCs alone groups); in the other two groups, a 'sham biopsy’ was performed to maintain patient blinding. All study products were injected transendocardially using the NOGA XP Mapping System (Biosense Webster, Madison, NJ, USA). Efficacy endpoints included heart failure-related MACE (all-cause death, hospitalization for worsening heart failure, or heart failure exacerbation that did not require hospitalization); quality of life, assessed by the Minnesota Living With Heart Failure questionnaire (MLHFQ) score; LV function and structure, assessed by MRI; functional capacity, assessed as peak VO2 and 6-min walking distance; and plasma levels of NT-proBNP.

Using an intention-to-treat analysis, the results showed a significant reduction in HF-MACE in patients receiving CPCs only or the combination of MSCs + CPCs, driven primarily by a reduction in hospitalization for worsening heart failure (Fig. 2). Compared with placebo, there was a relative 77% reduction in HF-MACE in the CPCs alone group (P = 0.043) and a 68% reduction in the MSCs + CPCs CPCs group (P = 0.061). The results of the as-treated analysis were similar (Fig. 3) (the as-treated analysis was conducted because in several patients the treatment administered was different from that of the group to which they were randomized). Significantly, the as-treated analysis showed that the 15 untreated patients had a similar outcome to the placebo-treated patients, therefore corroborating the results of the study (Fig. 3). Cox regression analysis showed a significant reduction in the incidence of HF-MACE in the CPC only group (hazard ratio vs. placebo, 0.20) and in the MSCs + CPCs group (hazard ratio, 0.26) (Fig. 4). In addition, quality of life, as measured by the MLHFQ score, was significantly improved at 6 and 12 months in the MSCs + CPCs group, and at 6 months in the MSCs alone group. There were no significant differences among groups in LVEF, LV volumes, scar size, peak VO2, 6-min walking distance, or NT-proBNP levels. Taken together, the results of CONCERT-HF suggest that in patients with chronic ischemic heart failure on maximal guideline-driven therapy, a single administration of autologous CPCs or MSCs has measurable beneficial effects over the ensuing 12 months, namely, a reduction in hospital-ization for heart failure (with CPCs) and an improvement in quality of life (with MSCs). The best overall results were obtained by combining MSCs with CPCs: reduced HF-MACE and improved quality of life [11,12▪▪].

F2FIGURE 2: Effects of autologous c-kit-positive cardiac cells, bone marrow mesenchymal stromal cells, and their combination on HF-MACE in the CONCERT-HF trial: shown are results of intention-to-treat analysis. Reproduced with permission [12▪▪].F3FIGURE 3: Effects of autologous c-kit-positive cardiac cells, bone marrow mesenchymal stromal cells, and their combination on HF-MACE in the CONCERT-HF trial: shown are results of as-treated analysis. Reproduced with permission [12▪▪].F4FIGURE 4: Effects of autologous c-kit-positive cardiac cells, bone marrow mesenchymal stromal cells, and their combination on cumulative incidence of HF-MACE in the CONCERT-HF trial: shown are results of intention-to-treat analysis. Reproduced with permission [12▪▪].

CONCERT-HF was the first trial that used CPCs manufactured according to Good Manufacturing Practices (GMP) standards. Since neither CPCs nor MSCs improved LV function or reduced scar size, the mechanism of action of these cells remains unclear. However, improvement in clinical outcomes without an improvement in LV function or a reduction in scar size is consistent with other studies, such as Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT) [13] and Ixmyelocel-T in Heart Failure Due to Ischemic Dilated Cardio-myopathy (ixCELL-DCM) [14] (Fig. 5). It is possible that the beneficial effects of CPCs and MSCs may be related to their anti-inflammatory and immuno-modulatory actions [15], consistent with the notion that chronic inflammation contributes to the progression of heart failure [16]. Other potential mechanisms include antifibrotic, proangiogenic, endothelial protective, or perhaps as-yet unknown actions of these cells [1▪,15]. This is undoubtedly the most important question currently facing investigators in the field of cell therapy.

F5FIGURE 5: Randomized, double-blind, Phase II or III trials that have found improvement in a hard endpoint (reduction in MACE) in patients treated with cell therapy despite lack of improvement in left ventricle function. ∗MACE: all-cause death, cardiovascular hospitalization, or heart failure exacerbation. #HF-MACE: all-cause death, heart failure hospitalization, or heart failure exacerbation. §MACE: cardiovascular death, myocardial infarction, or stroke. AT, as-treated analysis; ITT, intention-to-treat analysis. 1, Ref. [14]. 2, Ref. [12▪▪]. 3, Ref. [17]. Reproduced with permission [1▪].

Despite the uncertainty regarding the mechanism of action, CONCERT-HF suggests that CPCs and MSCs have disease-modifying properties in ischemic heart failure. The results of CONCERT-HF are very encouraging and certainly warrant follow-up, larger Phase III trials to definitively examine the efficacy of MSCs and CPCs.

DREAM-HF

The long-awaited results of DREAM-HF [17] have been recently presented in part [18▪▪], although at the time of this writing they have not been published. This is a very important study because it is the largest trial of cell therapy for heart failure to date. DREAM-HF was a randomized, double-blind, sham-controlled, Phase III study that involved 59 centers in North America. The study population consisted of 537 patients with high-risk, chronic ischemic or nonischemic heart failure (NYHA class II or III) on a stable, optimally tolerated guideline driven medical therapy for at least 1 month prior to randomization. The average LVEF was 28%. Patients were randomized to receive either transendocardial injection of 150 × 106 allogeneic BM-MSCs, which were immunoselected using anti-STRO-3 antibodies, or a sham catheterization procedure that did not include placebo. The duration of the follow-up varied because the study was event-driven, with a median of 30 months. The primary outcome was recurrent decompensated heart failure events.

There were no major adverse events except one incidence of LV perforation during LV mapping. Administration of MSCs did not reduce the primary endpoint. However, it did reduce prespecified secondary endpoints, including a 65% reduction in nonfatal MI or nonfatal stroke across all patients (P = 0.001) and a 57% reduction in cardiac death in NYHA II patients (P = 0.044) but not in the total population or in NYHA III patients. Mesenchymal precursor cells treatment resulted in a 33% reduction in the composite of cardiac death, nonfatal MI, or nonfatal stroke (P = 0.021), which appear to be entirely driven by patients with baseline elevated (2 mg/l) high-sensitivity C-reactive protein (hsCRP) (45% reduction, P = 0.012) [18▪▪].

The results of DREAM-HF are very encouraging. They show that a single administration of MSCs in patients with optimal guideline-driven therapy has beneficial effects on clinical outcome, including nonfatal MI, nonfatal stroke, and cardiac death after a median follow-up of 30 months. Although the mechanism is unclear, the MSCs used in this trial are known to have proangiogenic and anti-inflammatory properties [17]. It is possible that the beneficial effects observed in DREAM-HF reflect, at least in part, the ability of MSCs to reduce inflammation in large vessels throughout the body, thereby preventing MI and stroke, particularly since they were most apparent in patients with baseline inflammation (hsCRP  2 mg/l).

The results of DREAM-HF are important because, for the first time, a Phase III trial has demonstrated that cell therapy can beneficially affect hard clinical endpoints, such as cardiac death, MI, or stroke, in heart failure patients. It is noteworthy that these effects were observed after a single administration of cells and in patients who were on maximal guideline-directed medical therapy for heart failure. At present, DREAM-HF has not been published and some of the secondary endpoints, such as LV volumes and function, NT-proBNP, functional capacity, and quality of life have not been released. Despite these caveats, the results of DREAM-HF are provoking and warrant further investigation. Fortunately, the sponsor of DREAM-HF is planning a follow-up Phase III study targeted at patients with evidence of systemic inflammation (elevated hsCRP), in which the effect of MSCs on nonfatal MI, nonfatal stroke, and cardiac death will be the primary endpoint.

SENECA

SENECA was the first study that used cell therapy in patients with heart failure caused by anthracycline-induced cardiomyopathy [19,20]. This was a Phase I, randomized, placebo-controlled, double-blind, multicenter study sponsored by the CCTRN. It randomized patients to allogeneic BM-MSCs or placebo, both of which were injected by the transendocardial route. The study met its primary endpoints of safety and feasibility. The trial was small (31 patients) and therefore not powered for efficacy. Nevertheless, there was a significant improvement in functional capacity (measured as 6-min walking distance) and quality of life (measured as MLHFQ score) in patients treated with MSCs [20]. Other endpoints, including LV function and volumes, scarsize, NT-proBNP, were not signif-icantly different between the two groups. The results of SENECA are consistent with those of CONCERT-HF [11,12▪▪], ixCELL-DCM [14], and TAC-HFT[13], all of which suggest that cell therapy can produce clinical benefit without changes in LVEF. Overall, the results of SENECA are encouraging and warrant larger studies in patients with anthracycline-induced cardiomyopathy to assess the efficacy of cell therapy.

CONCLUSION

Contrary to the narratives that are frequently encountered in both scientific and lay publications, the results obtained heretofore in clinical trials of cell therapy in heart failure are encouraging and support continued investigation. Adult cell therapy is safe, and multiple randomized, placebo-controlled, double-blind studies have indicated beneficial effects of a single dose of cells in heart failure. With the exception of devices, no other heart failure therapy has shown disease-modifying properties for 12 months after a single dose. It seems plausible that repeated doses would be even more effective. Thus, larger, rigorous trials are warranted. Given the epidemic proportions of heart failure and the limitations of current therapies, it would be unreasonable, and possibly unethical, to halt clinical investigation of cell therapy in this population.

Acknowledgements

The current work was supported by National Institutes of Health grant P01 HL078825.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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