Time to End the War on Cell Therapy

This article refers to ‘Bone marrow-derived mesenchymal stromal cell treatment in patients with ischaemic heart failure: final 4-year follow-up of the MSC-HF trial’ by A.B. Mathiasen et al., published in this issue on pages 884–892. In this issue of the Journal, Mathiasen and colleagues report the final results of MSC-HF, a randomized, double-blind, placebo-controlled, Phase II study that evaluated transendocardial injection of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) in 60 patients with ischaemic heart failure (HF).1 At 12 months after MSC administration, there was a significant improvement in the primary endpoint [change in left ventricular end-systolic volume (LVESV)] relative to placebo (−17 mL; P < 0.0002). This was associated with an improvement, relative to placebo, in left ventricular ejection fraction (LVEF) (+6.2 units; P < 0.0001), myocardial mass (+9.8 g; P = 0.009), and quality of life. Interestingly, over the 4-year follow-up the incidence of angina was reduced in the MSC group. The MSC-HF trial is one of the best-designed studies of cardiovascular cell therapy performed to date. Overall, the 12-month results confirm and extend those reported previously at 6 months.2 The present paper1 is important because it indicates that, in patients with ischaemic HF, a single injection of autologous MSCs produces an improvement in left ventricular function and structure that is sustained for at least 12 months, and may be associated with clinical benefits for up to 4 years. The increase in LVEF (+6.2 units relative to control) was comparable to that effected by commonly used interventions such as early reperfusion in ST-elevation myocardial infarction or cardiac resynchronization therapy. Of note, MSC-HF utilized autologous BM-MSCs. Most cardiovascular trials nowadays use allogeneic MSCs, which may be more effective because they avoid the potential confounding effects of comorbidities.3 Given that transplanted cells do not differentiate into cardiomyocytes and do not survive more than a few weeks,4 it is remarkable that the salubrious effects of a single injection of BM-MSCs persisted for at least 12 months. Such a duration of benefit after one dose has not been observed with any medical therapy for HF. How a transient exposure to BM-MSC-secreted factors leads to long-term improvement is an important question for basic investigations; possible mechanisms include anti-inflammatory, anti-fibrotic, and anti-apoptotic actions of the secretome.4 An interesting aspect of this study is that BM-MSCs were not expanded beyond passage 2. Consequently, depending on the cell proliferation rate, patients received different numbers of cells, which enabled the authors to perform a dose–response analysis. The results demonstrate significantly greater reductions in LVESV and LVEF with doses >83 × 106 million cells (upper tertile) compared with the lower tertile (<43 × 106 cells). This positive relation between cell dose and outcome will be important for the design of future studies of MSCs. A number of considerations suggest that, for the treatment of chronic HF, BM-MSCs may be superior to BM unfractionated mononuclear cells (BM-MNCs). As shown in Table 1,2, 5-16 the studies of HF that have found benefit used BM-MSCs, not BM-MNCs. In TAC-HFT, BM-MNCs failed to confer the salubrious effects conferred by BM-MSCs (Table 1).7 Furthermore, FOCUS-CCTRN, a Phase II study of BM-MNCs, did not find a significant improvement in LVESV in a patient population similar to that of MSC-HF.17 Hare et al. (POSEIDON trial)5 ICM, LVEF <45% Improvements in total LV mass, MVO2 and wall motion score index Heldman et al. (TAC-HFT)7 ICM, LVEF <50% Autologous BM-MSCs; autologous BM-MNCs Mathiasen et al. (MSC-HF trial)2 Autologous BM-MSCs 77.5 ± 67.9 × 106 Patel et al. (ixCELL-DCM)8 Hare et al. (POSEIDON-DCM trial)9 Florea et al. (TRIDENT study)10 Allogeneic MSCs Autologous CD34+ cells after G-CSF × 5 days Losordo et al. (ACT34-CMI study)13 Povsic et al. (RENEW study)14b Autologous CD34+ cells after G-CSF × 5 days The final results of MSC-HF1 are important also because they appear at a time when hostility against adult cell therapy has reached new levels of stridor. Over the past few years, articles calling for a moratorium on all clinical trials of cell therapy have appeared. This position is epitomized by an anonymous and oft-cited editorial in Nature Biotechnology that claimed that cell therapy for cardiovascular disease is ‘futile’.18 As pointed out already,19 this editorial is misleading because it contains statements that are demonstrably incorrect, e.g. that no clinical trial of cell therapy has met its primary endpoint. In fact, several cardiovascular cell therapy trials have met their primary endpoint (Table 1). Specifically, three randomized, double-blind, placebo-controlled studies have demonstrated that administration of CD34+ cells to patients with refractory angina reduces angina (primary endpoint in ACT34-CMI13) and major adverse cardiovascular events and improves exercise time and quality of life.20, 21 Two Phase II, randomized, double-blind, placebo-controlled studies have shown beneficial effects of cell therapy in ischaemic HF. ixCELL-DCM (a Phase IIb multicentre trial in 109 patients at 31 sites) demonstrated a 37% reduction in the primary endpoint (death, cardiac hospitalization, acute decompensated HF).8 MSC-HF (discussed above) showed an improvement in the primary endpoint (left ventricular function) in 60 patients.1 These studies1, 2, 8, 20, 21 are definitely not ‘futile’. Recently, renewed calls to halt clinical investigation of cell therapy have followed the discovery of scientific misconduct in one basic research laboratory at Harvard, which has led to the retraction of several basic papers and one clinical paper reporting the SCIPIO trial. The rationale for the decision by The Lancet to retract the SCIPIO paper is published22 and exculpates all of the clinical work with cardiac c-kit positive cells, being limited to the figures, generated at Harvard, that illustrate the in vitro phenotype of the cells. The notice of retraction states: ‘…Although we do not have any reservations about the clinical work in Louisville that used the preparations from Anversa's laboratory in good faith, the lack of reliability regarding the laboratory work at Harvard means that we are now retracting this paper’.22 Should all clinical studies of cell therapy be stopped because of misconduct in one basic lab studying c-kit+ cardiac cells? This seems hardly to be the case. The data manipulation at Harvard is a tragedy, but it has nothing to do with clinical trials of BM-MSCs or CD34+ cells, nor does it justify halting investigation of novel therapies that are both safe and promising. This is where the field stands in 2020. What should we do now? Should we halt clinical trials because we do not know which cell type is ‘best’ and how exactly it works? Answering these questions in animal models may take several decades and besides, animal data may not be relevant to humans. The only clinically relevant data for a new therapy are those obtained in humans. Given that therapy with adult cells is safe, given the overwhelming evidence of efficacy at the experimental level, and given the encouraging Phase II data at the clinical level using CD34+ cells and BM-MSCs in the settings of refractory angina and chronic HF, respectively, it seems reasonable to evaluate cell therapy in these clinical settings with large, well-designed trials. This strategy is consistent with the overall position of the TACTICS group,25 the European Society of Cardiology,26 and the Food and Drug Administration.27 In fact, it could be argued that it would be unethical to halt clinical investigation of a therapy that so far has been safe and appears to be promising for the treatment of lethal or severely debilitating disorders. It is time to end the war on cell therapy and instead focus on obtaining conclusive data. The question as to whether cell therapy works will not be answered by stopping clinical trials. It will be answered only with rigorous, well-designed, adequately powered, and properly conducted Phase III studies. Conflict of interest: none declared.

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