Trials and tribulations of cell therapy for heart failure: an update on ongoing trials

Heart failure (HF) remains a leading cause of mortality, responsible for 13% of all deaths worldwide. The prognosis for patients with HF is poor, with only a 50% survival rate within 5 years. A major challenge of ischaemia-driven HF is the loss of cardiomyocytes, compounded by the minimal regenerative capacity of the adult heart. To date, replacement of irreversibly damaged heart muscle can only be achieved by complete heart transplantation. In the past 20 years, cell therapy has emerged and evolved as a promising avenue for cardiac repair and regeneration. During this time, cell therapy for HF has encountered substantial barriers in both preclinical studies and clinical trials but the field continues to progress and evolve from lessons learned from such research. In this Review, we provide an overview of ongoing trials of cell-based and cell product-based therapies for the treatment of HF. Findings from these trials will facilitate the clinical translation of cardiac regenerative and reparative therapies not only by evaluating the safety and efficacy of specific cell-based therapeutics but also by establishing the feasibility of novel or underexplored treatment protocols such as repeated intravenous dosing, personalized patient selection based on pharmacogenomics, systemic versus intramural cell delivery, and epicardial engraftment of engineered tissue products. Cell therapy has emerged in the past 20 years as a promising avenue for cardiac repair and regeneration. In this Review, Zhang and colleagues provide an overview of the evolution of cell-based and cell product-based therapies for the treatment of heart failure, including challenges and lessons learned, and summarize ongoing clinical trials on the feasibility of novel or underexplored treatment protocols. Historically, innovative therapies for heart failure (HF), such as implantable cardioverter-defibrillators and guideline-directed medical therapy, have taken nearly four decades to develop and were initially met with setbacks and scepticism; the field of cell-based therapy for HF is much younger and has similarly encountered numerous challenges and criticism from the scientific community.Findings from several randomized, double-blind, multicentre phase II and III trials published in the past 20 years support the concept that even a single dose of cell products has beneficial effects in patients with HF who are receiving optimal medical therapy.Ongoing clinical trials are examining novel cell types (including pluripotent stem cell-derived cardiomyocytes and umbilical cord-derived mesenchymal stromal cells), non-invasive cell delivery methods (intravenous injection), new protocols (repeated doses), new cell products (epicardial cardiomyocyte patches) and novel cell-free products (extracellular vesicle-enriched or exosome-enriched secretome) for cell-based therapy for HF.The results of these trials will continue to define and refine our understanding of cell-based and cell product-based therapies as a novel addition to guideline-directed medical therapy for patients with HF.