Browsing by Author "Taylor, Doris A."

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    Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients
    (Elsevier, 2020-11) Bolli, Roberto; Perin, Emerson C.; Willerson, James T.; Yang, Phillip C.; Traverse, Jay H.; Henry, Timothy D.; Pepine, Carl J.; Mitrani, Raul D.; Hare, Joshua M.; Murphy, Michael P.; March, Keith L.; Ikram, Sohail; Lee, David P.; O’Brien, Connor; Durand, Jean-Bernard; Miller, Kathy; Lima, Joao A.; Ostovaneh, Mohammad R.; Ambale-Venkatesh, Bharath; Gee, Adrian P.; Richman, Sara; Taylor, Doris A.; Sayre, Shelly L.; Bettencourt, Judy; Vojvodic, Rachel W.; Cohen, Michelle L.; Simpson, Lara M.; Lai, Dejian; Aguilar, David; Loghin, Catalin; Moyé, Lem; Ebert, Ray F.; Davis, Barry R.; Simari, Robert D.; Surgery, School of Medicine
    Background: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment. Objectives: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC. Methods: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 × 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers. Results: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group. Conclusions: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.
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    Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial
    (SAGE Publications, 2016) Taylor, Doris A.; Perin, Emerson C.; Willerson, James T.; Zierold, Claudia; Resende, Micheline; Carlson, Marjorie; Nestor, Belinda; Wise, Elizabeth; Orozco, Aaron; Pepine, Carl J.; Henry, Timothy D.; Ellis, Stephen G.; Zhao, David X. M.; Traverse, Jay H.; Cooke, John P.; Schutt, Robert C.; Bhatnagar, Aruni; Grant, Maria B.; Lai, Dejian; Johnstone, Brian H.; Sayre, Shelly L.; Moyé, Lem; Ebert, Ray F.; Bolli, Roberto; Simari, Robert D.; Cogle, Christopher R.; Department of Medicine, School of Medicine
    In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4(+) BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy-even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.
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    A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial
    (Wiley, 2021-04) Bolli, Roberto; Mitrani, Raul D.; Hare, Joshua M.; Pepine, Carl J.; Perin, Emerson C.; Willerson, James T.; Traverse, Jay H.; Henry, Timothy D.; Yang, Phillip C.; Murphy, Michael P.; March, Keith L.; Schulman, Ivonne H.; Ikram, Sohail; Lee, David P.; O’Brien, Connor; Lima, Joao A.; Ostovaneh, Mohammad R.; Ambale-Venkatesh, Bharath; Lewis, Gregory; Khan, Aisha; Bacallao, Ketty; Valasaki, Krystalenia; Longsomboon, Bangon; Gee, Adrian P.; Richman, Sara; Taylor, Doris A.; Lai, Dejian; Sayre, Shelly L.; Bettencourt, Judy; Vojvodic, Rachel W.; Cohen, Michelle L.; Simpson, Lara; Aguilar, David; Loghin, Catalin; Moyé, Lem; Ebert, Ray F.; Davis, Barry R.; Simari, Robert D.; Surgery, School of Medicine
    Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.
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    Recommendations for nomenclature and definition of cell products intended for human cardiovascular use
    (Oxford University Press, 2022) Taylor, Doris A.; Chacon-Alberty, Lourdes; Sampaio, Luiz C.; Gonzalez del Hierro, Mariana; Perin, Emerson C.; Mesquita, Fernanda C.P.; Henry, Timothy D.; Traverse, Jay H.; Pepine, Carl J.; Hare, Joshua M.; Murphy, Michael P.; Yang, Phillip C.; March, Keith L.; Vojvodic, Rachel W.; Ebert, Ray F.; Bolli, Roberto; Cardiovascular Cell Therapy Research Network (CCTRN); Surgery, School of Medicine
    Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term 'stem cell therapy' is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted haematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface-marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.