Multicenter cell processing for cardiovascular regenerative medicine applications: the Cardiovascular Cell Therapy Research Network (CCTRN) experience

Gee, Adrian P.; Richman, Sara; Durett, April; McKenna, David H.; Traverse, Jay H.; Henry, Timothy D.; Fisk, Diann; Pepine, Carl J.; Bloom, Jeannette; Willerson, James T.; Prater, Karen; Zhao, David; Koç, Jane Reese; Taylor, Doris A.; Cogle, Christopher R.; Moyé, Lemuel A.; Simari, Robert D.; Skarlatos, Sonia I.

doi:10.3109/14653249.2010.487900

Cited by 31 publications

(43 citation statements)

References 13 publications

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“…Briefly, the BM-MNC concentration was adjusted to produce a fixed dose of autologous cells, as described by Gee et al 7 . The target dose of BM-MNCs was 100 × 10 6 .…”

Section: Methodsmentioning

confidence: 99%

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

Taylor¹,

Perin²,

Willerson³

et al. 2016

Cell Transplant

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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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“…Briefly, the BM-MNC concentration was adjusted to produce a fixed dose of autologous cells, as described by Gee et al 7 . The target dose of BM-MNCs was 100 × 10 6 .…”

Section: Methodsmentioning

confidence: 99%

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

Taylor¹,

Perin²,

Willerson³

et al. 2016

Cell Transplant

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“…11 During the CCTRN TIME clinical trial, bone marrow was obtained from each participant's posterior iliac crest. This bone marrow was then combined with preservative-free heparin and transported at ambient temperature to a cell processing center at each clinical site.…”

Section: Methodsmentioning

confidence: 99%

“…9 BMC function was evaluated with 3 separate assays: the colony-forming unit Hill (CFU-Hill), the endothelial-colony forming cell (ECFC), and the colony-forming unit fibroblast (CFU-F) assays. 9, 11, 13, 14 The number of colony forming units, type of colonies, and percent confluency were recorded on days 7, 14, 21, and 28 for the ECFC and CFU-F assays and on days 4 through 9 for the CFU-Hill assay. Results from all 3 assays were assessed with the following 3 metrics: 1) slope of the best-fit linear curve for the percent confluency over time, 2) exponential constant of the best-fit exponential curve for the number of colonies over time, and 3) maximum number of colonies present over the entire culture period.…”

Section: Methodsmentioning

confidence: 99%

Bone Marrow Characteristics Associated With Changes in Infarct Size After STEMI

Schutt

Trachtenberg

Cooke

et al. 2015

Circulation Research

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Rationale Despite significant interest in bone marrow mononuclear cell (BMC) therapy for ischemic heart disease, current techniques have resulted in only modest benefits. However, select patients have shown improvements after autologous BMC therapy, but the contributing factors are unclear. Objective The purpose of this study was to identify BMC characteristics associated with a reduction in infarct size following STEMI. Methods and Results This prospective study comprised patients consecutively enrolled in the CCTRN TIME trial who agreed to have their BMCs stored and analyzed at the CCTRN Biorepository. Change in infarct size between baseline (3 days after percutaneous coronary intervention) and 6-month follow-up was measured by cardiac magnetic resonance imaging (cMRI). Infarct-size measurements and BMC phenotype and function data were obtained for 101 patients (mean age, 56.5 years; mean screening ejection fraction, 37%; mean baseline cMRI ejection fraction, 45%). At 6 months, 75 patients (74.3%) showed a reduction in infarct size (mean change, -21.0%±17.6%). Multiple regression analysis indicated that infarct size reduction was greater in patients who had a larger percentage of CD31+ BMCs (P=0.046) and in those with faster BMC growth rates in CFU-Hill and ECFC functional assays (P=0.033 and P=0.032, respectively). Conclusions This study identified BMC characteristics associated with a better clinical outcome in patients with STEMI and highlighted the importance of endothelial precursor activity in regenerating infarcted myocardium. Furthermore, it suggests that for these STEMI patients, myocardial repair was more dependent on baseline BMC characteristics than on whether the patient underwent intracoronary BMC transplantation. Trial Registration clinicaltrials.gov Identifier: NCT00684021

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“…(13, 14) Selected cell populations from the bone marrow enriched for angiogenic activities may provide a superior therapeutic effect (15) A subtype of hematopoietic progenitor cells has been isolated based on the presence of the cytosolic enzyme ALDH, a marker for stem and progenitor cells (Lin- CD34+CD38−). (16) This subpopulation of progenitor cells, called ALDH br cells, represents about 1% of total BMMNCs and contains a heterogeneous mixture of cell types thought to be needed for ischemic repair, including hematopoietic, endothelial, and mesenchymal progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

Perin¹,

Murphy

Cooke

et al. 2014

American Heart Journal

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Peripheral artery disease (PAD) is recognized as a public health issue because of its prevalence, functional limitations, and increased risk of systemic ischemic events. Current treatments for claudication, the primary symptom in PAD patients, have limitations. Cells identified usingcytosolic enzyme aldehyde dehydrogenase (ALDH) may benefit patients with severe PAD but has not been studied in patients with claudication. PACE is a randomized, double-blind, placebo-controlled clinical trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) to assess the safety and efficacy of autologous bone marrow–derived ALDHbr cells delivered by direct intramuscular injections in 80 patients with symptom-limiting intermittent claudication. Eligible patients will have a significant stenosis or occlusion of infrainguinal arteries and a resting ankle-brachial index <0.90 and will be randomized 1:1 to cell or placebo treatment with a 1-year follow-up. The primary endpoints are the change in peak walking time and leg collateral arterial anatomy, calf muscle blood flow, and tissue perfusion as determined by magnetic resonance (MR) imaging at 6 months compared to baseline. The latter 3 measurements are new physiologic lower extremity tissue perfusion and PAD imaging-based endpoints that may help to quantify the biologic and mechanistic effects of cell therapy. This trial will collect important mechanistic and clinical information on the safety and efficacy of ALDHbr cells in patients with claudication and provide valuable insight into the utility of advanced MR imaging endpoints.

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Multicenter cell processing for cardiovascular regenerative medicine applications: the Cardiovascular Cell Therapy Research Network (CCTRN) experience

Cited by 31 publications

References 13 publications

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

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

Bone Marrow Characteristics Associated With Changes in Infarct Size After STEMI

Rationale and Design for PACE: Patients with Intermittent Claudication Injected with ALDH Bright Cells

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