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. 2020 Nov;2(4):581-595.
doi: 10.1016/j.jaccao.2020.09.001. Epub 2020 Dec 22.

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial

Roberto Bolli  1 , Emerson C Perin  2 , James T Willerson  2 , Phillip C Yang  3 , Jay H Traverse  4 , Timothy D Henry  5 , Carl J Pepine  6 , Raul D Mitrani  7 , Joshua M Hare  8 , Michael P Murphy  9 , Keith L March  6 , Sohail Ikram  1 , David P Lee  3 , Connor O'Brien  3 , Jean-Bernard Durand  10 , Kathy Miller  11 , Joao A Lima  12 , Mohammad R Ostovaneh  12 , Bharath Ambale-Venkatesh  12 , Adrian P Gee  13 , Sara Richman  13 , Doris A Taylor  14 , Shelly L Sayre  15 , Judy Bettencourt  15 , Rachel W Vojvodic  15 , Michelle L Cohen  15 , Lara M Simpson  15 , Dejian Lai  15 , David Aguilar  16 , Catalin Loghin  17 , Lem Moyé  15 , Ray F Ebert  18 , Barry R Davis  15 , Robert D Simari  19 ; Cardiovascular Cell Therapy Research Network (CCTRN)
Affiliations

Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial

Roberto Bolli et al. JACC CardioOncol. 2020 Nov.

Abstract

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.

Keywords: cardiac repair; cardiooncology; chemotherapy; heart failure; stem cells.

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Conflict of interest statement

This work is supported by the National Institutes of Health (5 UM1 HL087318). All investigators received funding from the NIH National Heart, Lung, and Blood Institute (NHLBI) for conduct of the SENECA trial through the Cardiovascular Cell Therapy Research Network (CCTRN). Dr. Hare has held stock in Longeveron; has held stock and intellectual property in Vestion; and has a grant with Biologics Delivery Systems. Dr. Henry has served as a consultant for Biosense Webster. Dr. Pepine has served as a consultant for XyloCor, Caladrius, Imbria, and Biocardia; and has grants with Adelphi Values, Brigham and Women’s Hospital, Department of Defense, Gilead Sciences, Inc., McJunkin Foundation, Mesoblast, and Sanofi US. Dr. Perin has served as a consultant for Mesoblast. Dr. Taylor is co-founder of Stem Cell Security. Dr. Yang has served as a consultant for Terumo. Dr. Ebert has served as a staff member of the National Heart, Lung, and Blood Institute, the source of funding for the SENECA trial. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, National Institutes of Health, or the United States Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
NOGA Mapping and Injection Technique Left ventricular electromechanical 12-segment polar map representing Unipolar voltage. The scale (right) depicts voltage values represented by (visible light spectrum) color. The 20 injection sites of 0.4 ml each are represented by black dots. There is heterogenous distribution of lower voltage values (red) throughout the left ventricular endocardium likely representing areas of fibrosis. Injections were placed in areas of intermediate voltage between 4 and 8 mV and broadly distributed as per the injection strategy guidelines.
Figure 2
Figure 2
The SENECA CONSORT Diagram CONSORT diagram shows patients screened, enrolled, and treated in the SENECA trial, as well as number of patients that completed follow-up for each endpoint, along with reasons for noncompletion. 6MWT = 6-min walk test; AIC = anthracycline-induced cardiomyopathy; CMR = cardiac magnetic resonance; Allo-MSC = allogeneic mesenchymal stromal cells; HF = heart failure; LVEF = left ventricular ejection fraction; MLHFQ = Minnesota Living with Heart Failure Questionnaire; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association.
Central Illustration
Central Illustration
Key Elements of the Cardiovascular Cell Therapy Research Network’s SENECA Trial Key elements highlighted in the Cardiovascular Cell Therapy Research Network’s SENECA trial include the etiology of anthracycline-induced cardiomyopathy, in survivors of diverse cancers, and the notable findings demonstrating safety and feasibility of transendocardial administration allogeneic mesenchymal stromal cells.
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Comment in

  • One Small Step . .
    Piña IL. Piña IL. JACC CardioOncol. 2020 Nov 17;2(4):596-598. doi: 10.1016/j.jaccao.2020.10.003. eCollection 2020 Nov. JACC CardioOncol. 2020. PMID: 34396270 Free PMC article.

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