Letters to the Editor
Cell Therapy Strategies With No Safety Concerns and Demonstrated Benefits Warrant Study ― Reply ―
2020 Volume 84 Issue 11 Pages 2122-
Details
2020 Volume 84 Issue 11 Pages 2122-
Thank you again for the opportunity to share our review on cell therapy for heart disease.1 We are pleased that the readership has taken an interest in this topic and appreciate the letter from Drs. Pepine and Raval. We would like to commend their efforts in leading the CardiAMP Heart Failure trial, an ambitious and well-designed Phase III clinical trial in cardiac cell therapy.
The crux of our review is the distinction between contractile and non-contractile mechanisms of benefit. We believe that this biological distinction will affect efficacy, given the prominent role of cardiomyocyte deficiency in ischemic heart disease and other forms of heart failure. We fully recognize the potential for non-contractile cell strategies to have benefit. Non-contractile cell benefits such as modulation of innate immunity, cytoprotection, limiting fibrosis, and promoting angiogenesis do not appear to be specific to cell type, speaking to a more generalized benefit of cell therapy. Indeed, we expect that is an important, albeit secondary, mechanism of efficacy for contractile cells. While acknowledging the potential for non-contractile benefit, we also have to recognize that decades of clinical research with bone marrow and other non-contractile cells show little to no long-term improvement in cardiac function. In our view, these cells are safe, but they are not very potent. As such, we have chosen to develop a treatment for myocardial infarction that involves reconstitution of the lost myocardium.
To be sure, we make no claim of “success” in contractile cell therapy beyond the large animal studies performed by our group and others that demonstrate substantial remuscularization of the infarct and normalization of ejection fraction.2–4 We are unaware of any other investigational therapy for myocardial infarction that has achieved similar functional benefit. We caution readers to eschew the argument that true heart regeneration should not be pursued, simply because evolution has not selected it. By this argument, one also would reject angioplasty, β-blockers, ventricular assist devices, and virtually all other advances in cardiovascular medicine.
We anticipate rigorous preclinical and clinical investigation of contractile cell therapies in the coming years. As the authors of the letter mention and we acknowledge, pluripotent stem cell-derived cardiomyocyte transplantation presents several safety considerations less relevant for non-contractile cells that are short-lived, specifically, arrhythmogenicity, immunoreactivity and tumorigenicity. We believe that, although these challenges are inherent to any strategy of cardiac remuscularization, they can be systematically understood and managed.
Competition of ideas is part of a healthy biomedical ecosystem. None of us has sufficient time or resources to pursue all of the good ideas in cell therapy. Our group has chosen to explore remuscularization with human cardiomyocytes, while Drs. Pepine and Raval have chosen paracrine repair with bone marrow cells. We wish them much success and look forward to the results of the CardiAMP clinical trial and others under investigation. The most important goal is to bring to patients a well validated cell-based therapy with good safety and efficacy profiles. Going forward, consideration of underlying mechanism may help inform prespecification of endpoints and safety measures, and if we are lucky, allow our patients to teach us how to achieve clinical benefit.
C.E.M. is a scientific founder, equity holder, and employee of Sana Biotechnology. K.N. is a consultant for Sana Biotechnology.
