TWO EARLY-PHASE STUDIES REPORTED IN JAMA 1,2 ADdress the same general question: what is the effect of bone marrow–derived cell therapy on safety and surrogate end points in patients after myocardial infarction (MI)? Other than this thematic similarity, the Timing In Myocardial infarction Evaluation (TIME) trial and the POSEIDON trial have little in common. The TIME trial examined 120 patients with a recent (3-7 days) acute MI (AMI) and autologous mononuclear cells (MNCs) delivered via the intracoronary route with the intervention on day 3 (n=67) or on day 7 (n=53). This was a placebocontrolled, multicenter trial with a fixed dose of MNCs. The major motivation was to test the concept that timing of MNC therapy within the first week after MI influences outcome. The POSEIDON trial involved patients with ischemic cardiomyopathy after distant MIs (years earlier) and used autologous or allogeneic mesenchymal cells (MSCs) administered transendocardially via injection catheters. Two centers recruited 30 patients and randomly assigned them into 1 of 6 permutations of cell origin (self or donor) and dosage (n=5 patients each), with no controls. The goal of the trial was to compare the safety and efficacy of self-derived MSCs with donor MSCs in chronic ischemic cardiomyopathy. TIME is the latest in a series of studies from the Cardiovascular Cell Therapy Research Network (CCTRN), a consortium funded by the National Institutes of Health, which was mandated to conduct and complete trials of cell therapy within its initial 5-year funding period. Three trials (LateTIME, FOCUS-CCTRN, and now TIME) of autologous MNCs have been conducted. The goal of these trials has been to follow up on earlier positive phase 1 and 2 studies of MNCs; however, the CCTRN studies (including TIME) have all had negative results. The CCTRN used a convenient automated system for extracting MNCs from bone marrow aspirates. The older motivating studies, including the Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) multicenter trial of MNC therapy, relied instead on laborious manual Ficoll gradient centrifugation of bone marrow aspirates. TIME followed up on the subgroup analysis of REPAIR-AMI, hinting at superior functional outcomes in patients who had received MNCs more than 4 days after MI vs those who received therapy earlier. However, in TIME no significant incremental treatment effects on function, volumes, or infarct size were observed in patients treated with MNCs either 3 or 7 days after MI. The lack of benefit of MNC therapy in TIME and in the other CCTRN studies raises 2 possibilities: MNCs do not work, in which case the previous positive clinical studies were red herrings, or the CCTRN trials used an inactive cell product. The latter possibility cannot be discounted because MNCs isolated by the automated system used in this study have not been tested in an animal model of MI, and cell bioactivity has not been verified in any human studies of heart disease. In addition, the cell product used in TIME contained heparin at a dose that has been shown to impair the migratory capacity of MNCs. Such details of cell manufacturing are known to influence MNC potency substantially. Given these uncertainties, TIME (and the other 2 CCTRN studies) are well-intentioned, nicely designed, and impeccably executed, but difficult to interpret. POSEIDON, on the other hand, follows a more conventional development pathway, with ample preclinical validation and early proof-of-concept data in patients. The patients with chronic ischemic cardiomyopathy included in POSEIDON have a compelling clinical need. Their functional status is depressed and their ventricles have undergone extensive deleterious structural remodeling. The major finding of POSEIDON is that therapy with allogeneic (ie, donor-derived) MSCs appears to be safe and at least as active as therapy with autologous (ie, selfderived) MSCs. Allogeneic (but not autologous) MSCs reduced end-diastolic volume, whereas both allogeneic and autologous MSCs reduced early enhancement defect (a controversial measure of infarct size derived from computed tomography). The apparent changes in myocardial structure were not matched by improvements in global ventricular function; neither allogeneic nor autologous MSCs showed any significant increase in ejection fraction when analyzed individually or pooled together.
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