Cell Therapt for Cardia Repair Lessons From Clinical Trials

Stem cell therapy holds promise for chronic heart failure (CHF) management as animal studies document that these cells modify local inflammatory conditions, release factors that stimulate angiogenesis and intrinsic tissue repair, modify adverse ventricular remodeling, and restore function.¹ Clinical trial results, however, are more variable with some showing beneficial effects and others without.^2,3 Preclinical studies are conducted in otherwise healthy animals, but clinical studies enroll CHF patients with multiple comorbidities (aging, diabetes mellitus, hypertension, inflammation, etc) that negatively affect regenerative capacity.⁴ Significant variability in regenerative response is linked with variations in cell characteristics (eg, migratory and adhesion capacity, clonogenicity, surface marker expression, and paracrine factor release).^5,6 Using a personalized medicine approach (ie, tailoring treatment to patient characteristics to optimize benefit), we propose to optimize cardiac cell therapy efficacy by prospectively selecting patients most likely to benefit using a cell potency assay to assess inherent regenerative capacity.^7,8

Variability of Stem Cell Therapeutic Potency and Patient Regenerative Capacity

The majority of cardiac stem cell trials to date used autologous bone marrow cells (BMCs). Yet, functional properties of BMCs vary across patients, and comorbidities negatively affect cell characteristics.^4,9–11 CHF also negatively affects BMC function, with lower rates of colony formation units and response to erythropoietin stimulation versus age-matched controls.¹² Although patients may receive the same number (ie, dose) of autologous BMCs, the therapeutic potency of those cells can vary widely from patient to patient, and this likely accounts, in part, for the observed variation in effect.

One solution is to use allogeneic cells from a therapeutically potent donor, but even optimal cells may not provide benefit if the recipient's regenerative capacity is poor. It was suggested that although the focus in stem cell trials is typically on the administered cells, there is little on the patient and tissue targeted for regeneration.⁷ Indeed, there is evidence that the variable cell potency observed across patients in clinical trials reflects not just the quality of delivered cells but also the underlying regenerative capacity of the treated patient.^6,13 With the growing understanding that stem cell therapy functions to a large extent via paracrine mechanisms,^3,8 it seems clear that the recipient's regenerative capacity is likely a critical determinant of therapeutic effect.

To develop criteria that identify patients likely to benefit from regenerative therapies, it is important to identify functional indices associated with improved outcomes. Analyses from some trials support the importance of cell and patient characteristics in predicting clinical outcomes. In FOCUS-HF (First Bone Marrow Mononuclear Cell United States Study in Heart Failure) assessing effects of intramyocardial autologous bone marrow mononuclear cells in patients with no option CHF, younger patients (≤60 years) had significantly higher numbers of mesenchymal progenitor cells versus those >60 years. Younger patients also had significant improvement in maximal oxygen consumption (VO₂max) versus age-matched reference subjects while older patients did not, identifying age as an important modifier of therapeutic effect.⁹ In LATE-TIME (Late Timing in Myocardial Infarction), patients with left ventricular (LV) ejection fraction ≤45% received intracoronary autologous BMCs or placebo 2 to 3 weeks after reperfused ST-segment–elevation myocardial infarction. Although the overall results did not show benefit, the prevalence of CD34+, CD133+, and CD45+/CXCR4^dim (C-X-C chemokine receptor 4) cells and higher endothelial colony formation units correlated with improved LV function.¹⁰ In addition, comorbidities negatively altered BMC composition, function, and surface marker expression. Last, in the TIME trial (Timing in Myocardial Infarction), patients received intracoronary autologous BMCs or placebo 3 or 7 days post–ST-segment–elevation myocardial infarction. Infarct size reduction at 6 months was correlated with CD31+ cell number and colony formation unit,⁵ suggesting additional predictive markers.

Markers of Intrinsic Regenerative Capacity

Other studies suggest significant variation in intrinsic regenerative capacity, which could be useful to identify likely responders versus nonresponders. In FOCUS-CCTRN (First Mononuclear Cells Injected in the United States Study Conducted by the Cardiovascular Cell Therapy Research Network), patients with chronic ischemic cardiomyopathy received transendocardial delivery of autologous BMCs or placebo. Patients with improved LV ejection fraction, LV end-systolic volume, and VO₂max at 6 months (responders) were compared with patients failing to respond in at least 1 measure (nonresponders).⁶ Irrespective of treatment, responders had higher frequencies of B-cells and CXCR4+ BMCs, with fewer endothelial cell colony formation units and macrophages, suggesting a BMC profile of patients with superior regenerative capacity. Similarly, in the PERFECT trial (Intramyocardial Transplantation of Bone Marrow Stem Cells for Improvement of Post-Infarct Myocardial Regeneration in Addition to CABG Surgery), patients with ischemic cardiomyopathy received intramyocardial autologous CD133+ BMCs or placebo at coronary revascularization surgery.¹³ Patients without LV functional improvement after revascularization, regardless of treatment, had lower preprocedural levels of CD133+, CD34+, CD117+ endothelial progenitor cells and thrombocytes, with increased erythropoietin and SH2B3 gene expression in peripheral blood. Responders to CD133+ cell therapy had lower levels of preprocedural vascular endothelial growth factor, erythropoietin, and CXCL10 (C-X-C motif chemokine 10). Using these biomarkers, preprocedural predictive accuracy for responders and nonresponders approximated 80%.

Prospective Analysis of Regenerative Capacity

These studies suggest that biomarkers and functional assays may be helpful to identify, a priori, cells and recipients with a higher capacity for tissue regeneration. But instead of retrospective identification of advantageous biomarker profiles, the ultimate goal is prospective identification of patients likely to respond to cell therapy. With evidence of variability in autologous stem cell therapeutic potency and intrinsic regenerative potential, and multiple readily identifiable markers associated with improved outcomes, there is opportunity to develop potency assays to guide trial design and patient enrollment. Indeed, this was a priority identified by the European Committee for Advanced Therapies for cell-based therapies targeting cardiac repair.⁸ Conversely, identification of patients with poor regenerative capacity could drive development of novel approaches to ameliorate this deficiency.

The CardiAMP Heart Failure trial, a randomized, double-blind pivotal study enrolling patients with ischemic cardiomyopathy, LV ejection fraction 20% to 40%, is the first to incorporate a cell potency score in screening criteria.¹⁴ In addition to standard screening studies, including 6-minute walk distance, New York Heart Association heart failure classification, and Minnesota Living with Heart Failure Questionnaire, patients undergo screening mini-bone marrow aspiration to measure surface marker expression and functional properties in an assay devised to identify therapeutically potent BMCs. Patients meeting the potency assay requirement are randomized to transendocardial autologous bone marrow mononuclear cells or a sham procedure. The goal is a high effective cell dose, that is, a high number of bone marrow mononuclear cells(target 2×10⁸) isolated from selected patients and administered with efficient intramyocardial delivery by Helix/Morph injection system. The primary outcome is change in 6-minute walk distance adjusted for major adverse cardiovascular events at 12 months.¹⁴ Banked BMC samples will allow additional analyses of responders and nonresponders. Enrollment is complete in the 10-patient open-label Roll-In cohort, and 6-month follow-up shows improved 6-minute walk distance (+47.8 m±19.6; 20.5% relative improvement; P=0.01) and New York Heart Association class (P=0.037) and a positive trend in Minnesota Living with Heart Failure Questionnaire Score (−10.2±7.9; 31% relative improvement; P=0.21; see Figure). Enrollment is now active in the randomized phase of the study (goal 250 patients).

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Figure. Six-month open-label CardiAMP Roll-In cohort results (n=10). A, Change in 6-minute walk distance (6MWD), (B) change in New York Heart Association (NYHA) heart failure class, and (C) Minnesota Living With Heart Failure Questionnaire (MLHFQ).

Conclusions

Delivery on the promise of cardiac regenerative therapy will require development of novel strategies leveraging knowledge gained in prior trials to prospectively identify patients likely to respond to therapy and optimize therapeutic potency through evidence-based cell characterization, preparation, and delivery. CardiAMP-HF is a first step in this direction. We believe that trials offering more specific, patient-centered, and personalized approaches to regenerative medicine will generate the robust and effective therapies needed to address CHF and other conditions.

Sources of Funding

CardiAMP-HF is funded by BioCardia, Inc, San Carlos, CA, and by the Maryland Stem Cell Research Fund (2016-MSCRFP-2804). C.J. Pepine receives funding from the Cardiovascular Cell Therapy Research Network NIH/NHLBI UM1 HL087366.

Disclosures

P.V. Johnston, A.N. Raval, and C.J. Pepine are members of the Executive Steering Committee for CardiAMP-HF and receive consulting fees and grant support for their services. H.J. Duckers is an employee of BioCardia, Inc and holds equity interest in the company. The other author reports no conflicts.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Correspondence to Peter V. Johnston, MD, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Bldg No. 1167, 720 Rutland Ave, Baltimore, MD 21287. Email [email protected] edu

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Cell Therapt for Cardia Repair Lessons From Clinical Trials

Source: https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.118.313425

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