Mesenchymal Stem Cells as a biological drug for heart disease: Where are we with cardiac cell-based therapy?

Abstract

Cell-based treatment represents a new generation in the evolution of biological therapeutics. A prototypic cell-based therapy, the mesenchymal stem cell (MSC), has successfully entered phase III pivotal trials for heart failure, signifying adequate enabling safety and efficacy data from phase I and II trials. Successful phase III trials can lead to approval of a new biologic therapy for regenerative medicine.

The use of stem or progenitor cells therapeutically is under investigation for the treatment of chronic diseases, including cardiovascular pathologies.¹ Not unusual for an early stage disruptive technology, early findings have led the field to an important and controversial cross-roads. Based in large part on disagreements surrounding mechanism of action of cell-based therapy, some authors have called for a reappraisal of the existing data, while others have concluded that the field has “evolved too quickly into clinical practice” and that we “need to go back to the bench”.² However, there are many historical examples including the notable examples of aspirin and opioids that were employed therapeutically before the mechanisms of actions were fully understood. In the midst of this debate regarding mechanism of action of cell therapy, an emerging field of investigation that holds great promise needs to be highlighted. In this context, the development of MSCs has followed the characteristic trajectory of preclinical and clinical development, supported by data highly predictive of successful therapeutic outcome. Most importantly, because of its allogeneic potential, MSCs can be viewed as a true cellular biological therapy with the capacity for high volume quality-controlled production and “off the shelf” usage.³

What are MSCs?

MSCs are mesoderm-derived multipotent stromal cells that reside in embryonic and adult tissues, prototypically bone marrow. Having the capacity for self-renewal, MSCs maintain stemness (e.g. multipotency) and exhibit immune-privileged, immunomodulatory, and pro-regenerative proprieties due, in part, to their secretome.¹ As such, culture-expanded MSCs represent a controlled and homogeneous stem cell population.

Why MSCs became one of the top choices?

A large majority of early cell-based clinical trials for heart disease were designed for acute myocardial infarction (AMI) and conducted using autologous bone marrow mononuclear cells (BM-MNCs). The widespread use of BM-MNCs can be attributed to immediate cell availability from the recipient. However, the efficacy was variable. Using global left ventricular ejection fraction (LVEF) as an endpoint, BM-MNC trials showed controversial results, and later trials tended to be negative.⁴ Perhaps, one of the factors contributing to this discordance was the innate diversity of cell populations found in isolated BM-MNCs between patients. All this has led to the search of more specific stem cell subpopulations with more specific identifying characterizations. Particularly, the field needed an adult stem cell that is easy to isolate, culture, and manipulate in ex vivo conditions. In this regard, MSCs, in part, due to their long standing record in regenerative medicine, proven safety and potency, have emerged as a lead candidate cell type with accumulating clinical investigations employing this stem cell population for AMI and chronic heart failure.⁵

What was trajectory of preclinical and clinical development of MSCs?

Following experiments in rodents, multiple preclinical studies in different animal models of acute and chronic heart failure have been conducted, which together demonstrate favorable impact on left ventricle (LV) remodeling, driven largely by a 30–50% reduction in infarct scar size.⁶ Accumulating data led to Food & Drug Administration (FDA) approval for testing MSC-therapy in early phase small clinical trials (pilot studies) that established the safety of both autologous and allogeneic MSCs.⁷ The pilot studies have, in turn, guided the design of phase II clinical trials suggesting the optimal use of stem cells, delivery methods, and cost–effective way to investigate clinical efficacy.

MSC as a therapeutic agent

It is valuable to consider MSC-based therapy in the context of general principles of therapeutic development. On the average, it takes 12 to 15 years and up to $5 billion to develop and launch a new drug. Given this paradigm, the decade of work on developing MSCs cannot and should not be dismissed. While only 1 out of 10 investigational new drugs succeeds from phase I to FDA approval, the probability of success increases with the transition to later stages of clinical trial development.⁸ MSCs have decisively passed phase II, a rigorously controlled phase, and have recently entered phase III trials.¹ New therapeutic development often must encounter “The Valley of Death”, which is a translational research gap during which time safety assessments for chemical and biological drugs are made. This period can often be intensified if animal models for the disease in question have deficiencies.⁹ As a consequence, the attrition rate of drugs entering human trials even after passing pre-clinical translational research in animal models remains very high, representing 90% in all areas.¹⁰ Hence, it should be noted that substantial preclinical data supporting MSCs in the injured heart has emerged from highly representative large animal models, such as the porcine, which has similar cardiac anatomy and physiology as humans.¹¹ The remodeling process in these models is highly reminiscent of LV remodeling in humans and has accurately predicted phenotypic outcomes in clinical trials. Experiments in porcine models have been used to test both human cells in immunosuppressed animals ⁶ as well as autologous cells.¹²

Reasons for failure of a new therapeutic strategy

The generic reasons that explain the failure of a new therapeutic include: poor understanding of drug pharmacology,¹³ poor linkage between molecule-to-disease,¹⁴ and variability in the underlying genetics/epigenetics in animals and humans.¹⁵ MSC pharmacology has proven mechanisms of action which include MSC plasticity, secretion of numerous bioactive molecules, exosomes and mitochondria transfer. These bioactive molecules, in turn, promote myocardial tissue growth through endogenous activation of angiogenesis, neurogenesis, immunomodulation, cardiac stem cell and mature cardiomyocyte proliferation.¹ With regard to genetics/epigenetics in animals and humans, the use of human cells in animal models has justified the safety and potency of human MSCs, demonstrating that these cells are capable of replacing tissue loss and restoring cardiac function.⁶ The use of allogeneic MSCs was initiated in animal models as well, contributing to a better understanding of the interdisciplinary nature of MSC biology particularly immune privilege proprieties that supported future studies in humans.

Where are we now with regard to clinical trials of MSCs?

Since 2011, MSCs and related culture-expanded cell preparations have been tested in small trials for chronic heart failure. These trials have consistently shown that cell therapy in this clinical setting reduces MI scar size, reverses ventricular remodeling, improves 6-minute walk distance and quality of life, as measured with validated questionnaires (Table 1).^16–20 Nevertheless, while multiple meta-analyses have debated whether or not the degree of cardiac functional improvements, including increases in LVEF, are significant,² there are not enough standardized clinical trials studying MSCs or related cells with appropriate sample sizes to confidently answer this question. A review of trials registered on clinicaltrials.gov revealed 34 MSC clinical trials for adult heart pathology (AMI, ischemic and non-ischemic chronic heart failure). Most studies remain in Phases I and II (Figure 1A) but there are several Phase III trials currently underway or completed (Table 2).²¹ A major issue of note is the diversity of MSC clinical trials. Seven of these trials are multi-centered and one is double-centered. Most of them (27) are small-sized trials, enrolling less than 100 patients per trial (Figure 1B, 1C) and only some are placebo-controlled. The MSC route of administration (intravenous, intracoronary, intramyocardial, transendocardial) (Figure 1D), cell dose, and cell origin (fetal-umbilical vs. adult, autologous vs. allogeneic, bone-marrow vs. adipose derived) are dissimilar in these clinical trials as well. Indeed, it is crucial to mention that MSC origin and location may define MSC characteristics and therefore influence MSC behavior.^{3, 22} These facts highlight the variability in MSC clinical trials, specifically with respect to study design, cell origin and dose/delivery methods. In 2009, the first double-blinded allogeneic MSC clinical trial for AMI sponsored by Osiris demonstrated that intravenous infusion of allogeneic MSCs was well tolerated and lowered arrhythmic events and chest pain.⁷ This trial started the era of allogeneic MSCs for heart disease and today, allogeneic MSC products are used in large clinical trials with enrollment targets in the 1000s of patients. Success with these efforts could lead to approval of these products by the FDA.

Table 1.

Trials of cell-based therapy in chronic heart failure

Trial Name [reference] (# patients)	Δ6MWT	ΔMLHFQ	ΔMI SIZE	ΔEF
Williams et al. [6] (n=8)			−18.3±8.3%
SCIPIO [20] (n=21)		−19.8	−9.8 ±3.5 g (−30%)	+8–12.3%
MESOBLAST* (n=60)	+50.8 m†			+7.0%
CADUCEUS [18] (n=25)	+33.0 m	−10.8**	−12.9 g (−42%)	**
POSEIDON [16] (n=30)	+43.5 m	−7.6	−33.21%	+2.0%**†
C-CURE [19] (n=33)	+62.0 m	±10**†		+7.0%
TAC-HFT [17] (n=59)	+32.6 m**	−6.3	−12.6 g (−32.9%)	**
MSC-HF* (n=59)			−4.4 ± 5.1 g	+5.5 ± 3.8%

^*Data not published

^**Not significant within-group

^†Not significant vs. control

6MWT- 6-minute walk test; MLHFQ-Minnesota Living With Heart Failure Questionnaire; MI SIZE- myocardial infarction size/ scar size; EF- ejection fraction

Figure 1. 34 MSC clinical trials for heart disease.

Number of MSC clinical trials according trial phase (A). Total number of patients enrolled or estimated to be enrolled according trial phase (B). Average number of patients enrolled or estimated to be enrolled per trial (C). The route of cell administration in 35 clinical trials (intravenous (IV), intracoronary (IC), intramyocardial (IM), transendocardial (TE)) (D).

Table 2.

Phase II/III and III clinical trials of cell-based therapy in heart disease

Trial ID [reference] Trial location # of patients	Trial Name (trial stage)	Cardiac Pathology	Delivery Method	Cell type	Sponsor	Primary Endpoints
NCT01753440 Greece 30 (estimated)	Allogeneic Stem Cells Implantation Combined With Coronary Bypass Grafting in Patients With Ischemic Cardiomyopathy (On-going)	Ischemic Cardiomyopathy + CABG	Intramyocardial/itraoperative	Allogeneic MSCs	AHEPA university Hospital	Change in LVEF by EchoCG and Myocardial segmental perfusion
NCT01392105 [21] Republic of Korea 80 (final)	Safety and Efficacy of Intracoronary Adult Human Mesenchymal Stem Cells After Acute Myocardial Infarction (SEED-MSC) (Completed)	Acute Myocardial Infarction	Intracoronary	Autologous Human Bone Marrow Derived MSCs	Yonsei University, collaboration with FCB- Pharmicell Co., Ltd	Absolute change in global LVEF by SPECT
NCT01394432 Russia 50 (estimated)	ESTIMATION (On-going)	Acute Myocardial Infarction Heart Failure	Catheter-based transendocardial delivery	Autologous Human Bone Marrow Derived MSCs	Meshalkin Research Institute of Pathology of Circulation	Change LVESV and LVEDV by MRI
NCT01652209 Republic of Korea 135 (estimated)	RELIEF (On-going)	Acute Myocardial Infarction	Intracoronary	Autologous Human Bone Marrow Derived MSCs	Pharmicell Co., Ltd	Change LVEF by MRI
NCT02032004 US and Canada 1730 (estimated)	Allogeneic Mesenchymal Precursor Cells (CEP-41750) for the Treatment of Chronic Heart Failure (On-going)	Chronic Heart Failure (Ischemic and Non-Ischemic)	Catheter-based transendocardial delivery	Allogeneic Mesenchymal Precursor Cells (CEP- 41750)	Teva Pharmaceutical Industries	HF-MACE
NCT00810238 [19] Belgium, Serbia 33 (final)	C-CURE (Completed)	Chronic heart failure secondary to ischemic cardiomyopathy	Catheter-based transendocardial delivery	Autologous bone marrow– derived and cardiogenically oriented MSCs	Cardio3 BioSciences	Change in LVEF
NCT01768702 Belgium, Hungary Israel, Italy Poland, Serbia Spain, Sweden Switzerland United Kingdom 240 (estimated)	CHART-1 (On-going)	Chronic Advanced Ischemic Heart Failure	Catheter-based transendocardial delivery C-Cath® injection catheter	Autologous Bone Marrow- derived Mesenchymal Cardiopoietic Cells (C3BS-CQR- 1)	Cardio3 BioSciences	MLHFQ 6 min walk test LVESV (absolute change ≥4%) in LVEF
NCT02317458 No location provided. 240 (estimated)	THE CHART-2 TRIAL (Not recruiting)	Congestive Heart Failure secondary to ischemic cardiomyopathy	Catheter-based transendocardial delivery	Autologous Bone Marrow- derived Mesenchymal Cardiopoietic Cells (C3BS-CQR- 1)	Cardio3 BioSciences	6 min walk test

LVEDV –Left ventricular end diastolic volume; LVESV-Left ventricular end systolic volume; MRI- Magnetic resonance imaging;

EchoCG-Echocardiogram; SPECT-Single-photon emission computed tomography;

HF-MACE-Heart failure-related Major Adverse Cardiac Events;

MLHFQ-Minnesota Living with Heart Failure questionnaire

MSC therapy perspectives

Given all of the above, MSC clinical trials have already crossed the Rubicon suggesting that cell-based therapy is safe, efficient, and efficacious. Biological drugs such as stem cells have a more arduous path to travel compared to their chemical counterparts. The nature of a biological drug is more complicated and in addition to safety and efficacy, raises ethical, political, and economic concerns that need to be addressed. MSCs are overcoming the majority of these challenges and several efforts have resulted in phase III clinical trials that, if successful, could lead to approval. There are still unresolved issues regarding cell dose and number of treatments needed to reach the desired results. It is unclear whether MSC donors can influence cellular product efficacy. We certainly need to follow the established quality control standards for MSC products and define the patient population that is eligible and will benefit the most from cell therapy.

In conclusion, MSC-based therapy for heart disease can be viewed in the context of a novel class of biological therapeutics and one that is following a characteristic drug development pipeline. Appropriate preclinical models have been used that can predict findings in humans and ensure safety. Finally, allogeneic MSC products, a biological drug with standardized quality controlled manufacturing, are demonstrated to be safe and effective in phase I and II clinical trials for AMI and chronic heart failure.^{7, 16} The current ongoing conduct of phase III trials are warranted and could lead to product approval. Enlarging efforts to conduct phase II and III trials should be encouraged and will contribute to advancing this field which has the potential to address large unmet medical needs and substantially influence human health.

Nonstandard abbreviation and Acronyms

6 MWT

6-minute walk test

AMI

acute myocardial infarction

BM-MNCs

bone marrow mononuclear cells

EchoCG

Echocardiogram

EF

ejection fraction

FDA

Food & Drug Administration

HF-MACE

Heart failure-related Major Adverse Cardiac Events

LV

left ventricle

LVEDV

Left ventricular end diastolic volume

LVEF

left ventricular ejection fraction

LVESV

Left ventricular end systolic volume

MI SIZE

myocardial infarction size/scar size

MLHFQ

Minnesota Living with Heart Failure questionnaire

MRI

Magnetic resonance imaging

MSCs

mesenchymal stem cells

SPECT

Single-photon emission computed tomography