Letters to the Editor
Cell Therapy Strategies With No Safety Concerns and Demonstrated Benefits Warrant Study
2020 Volume 84 Issue 11 Pages 2120-2121
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2020 Volume 84 Issue 11 Pages 2120-2121
To the Editor:
Heart failure (HF) in ischemic heart disease is epidemic, consumes enormous healthcare resources, and necessitates new therapies. We applaud the “review of cell therapy”,1 with excitement for the cells that they champion from animal studies exploring repopulation of infarction through direct regeneration.
However, we were struck by their message that only cardiomyocytes had a solid footing from a mechanism of action perspective, and thus the only cells worth investigating. They state that non-contractile cells, such as bone marrow-derived cells (BMDCs), “offer little functional benefit to infarct patients”, and focus should turn to cells with potential to directly induce remuscularization.
They acknowledge potential benefits of BMDCs, because most (non-contractile) cell types exert salutary paracrine effects when transplanted into acutely infarcted hearts, as supported by meta-analyses of BMDC trials like TAC-HF,2,3 which support safety with suggestions of functional benefit in ischemic cardiomyopathy.
Autologous BMDCs in Phase III trials4,5 shouldn’t be dismissed solely because they don’t provide new cardiomyocytes, as salutary effects are not likely tied only to cardiomyocyte repopulation.6 Similarly, it would be inappropriate to call preclinical contractile therapies “successes” until they are thoroughly tested in patients and critically important safety issues of immunosuppression, tumorogenesis and arrhythmogenesis are resolved. This last point may be the most daunting challenge because evolution itself may have chosen not to repopulate lost cardiomyocytes given their potential to become ectopic foci.
An alternative strategy for post-infarction HF would be to modify healing to reduce continuing cell death, fibroblast proliferation, and collagen deposition with loss of contractility and adverse remodeling. Analysis of some of the rigorous data sets on BMDCs shows promise. Although CCTRN-FOCUS7 used 100 million autologous BMDCs and did not meet primary efficacy endpoints, two of its components numerically favored benefit (reduced LV end-systolic volume (LVSV), increased maximal oxygen consumption), and the increase in LV ejection fraction (EF) was statistically significant. Post hoc analysis suggested those receiving higher doses of CD34+ and CD133+ cells benefited with greater EF increases. Additionally, the Phase II TAC-HFT trial2,3 met its primary safety endpoint of no treatment-emergency major adverse cardiac events at 30 days with statistically significant improvements in 6-minute walk distance and quality of life (QOL). The TAC-HFT trial used a higher dosage and more efficient delivery system5 to target a 6-fold higher effective dose of BMDCs8 vs. CCTRN-FOCUS. Furthermore, benefits in TAC-HFT were comparable and, for some endpoints, superior to those in pivotal trials for cardiac resynchronization.9 Combined, these BMDC trials, with signals from the ACT34 and RENEW trials,4 led to the ongoing Phase-III CardiAMP-HF trial5 using BMDCs in a “personalized medicine approach”. This trial requires a preprocedural assay to select patients with a favorable “bone marrow cell score” based on CD34+ progenitor cells and other proprietary factors derived from proven responders in CCTRN-FOCUS and other trials. It uses the highly efficient delivery system with a strong safety profile employed in the TAC-HF trial.
CardiAMP-HF reported 10 “roll-in phase” patients10 treated with BMDCs and found the approach feasible with no safety issues. Although not powered for efficacy, at 12 months there was significant improvement in total wall motion score and numerically increased LVEF, LVSV, exercise capacity, and QOL vs. baseline. Trends toward improvement in measures important to patients (i.e., exercise capacity, QOL through symptom relief, and heart function) are an achievement for cell-based therapy. Exercise capacity and QOL improvements over baseline exceeded those from TAC-HFT. Furthermore, after 50 patients the Data Safety Monitoring Board found no safety issues, recommending the trial continue as planned.
Such cell therapy approaches, not aimed at repopulating cardiomyocytes, are the only cell therapies with clinical experience. It is believed that they facilitate natural repair responses of BMDCs homing to injury in chronic HF where homing signals have either dissipated or were inadequate. These approaches support technologies related to intramyocardial cell delivery and fusion imaging for guiding cell deliveries valuable to those actively working to repair/repopulate myocardium. It is imperative to encourage high-quality investigations of BMDCs such as CardiAMP-HF.
Patients with HF have few attractive options today and deserve the best of all of our efforts. Cell therapy strategies with no safety concerns and demonstrated benefits are worth advancing in rigorous clinical studies, even if they do not provide new cardiomyocytes.
C.J.P. and A.N.R. are consultants to BioCardia and Co-National Principal Investigators of the CardiAMP Heart Failure Trial. A.N.R. receives research support from Siemens Healthcare and research funding from the National Institute of Health.
None.
