Linking cell function with perfusion: insights from the transcatheter delivery of bone marrow-derived CD133+ cells in ischemic refractory cardiomyopathy trial (RECARDIO)

Abstract

BackgroundCell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function.MethodsIn the phase I “Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy” (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ≤ 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations.ResultsPatients were treated safely with a mean number of 6.57 ± 3.45 × 106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 ± 8.6 to 13.8 ± 7.8, p = 0.05) and difference scores (from 12.0 ± 5.3 to 6.1 ± 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 ± 2.2 to 4.0 ± 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p ≤ 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = − 0.79, p = 0.01) and IL-6 (r = − 0.76, p = 0.02).ConclusionResults of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations.Trial registrationClinicalTrials.gov, NCT02059681. Registered 11 February 2014.

Son of a Lesser God: The Case of Cell Therapy for Refractory Angina

“…Indeed, a consistent body of evidence (RCT and MTA) cumulatively indicated that CT is safe and can effectively increase physical function and well-being by reducing angina symptoms and drug assumption in the absence of relevant side effects ( 18 ). Different pro-angiogenic cells were administered in an autologous setting, including unfractioned bone marrow (BM)-derived mononuclear cells (MNC) ( 99 , 100 ), selected endothelial progenitors (i.e., CD34 + and CD133 + cells) derived from BM or peripheral blood ( 101 – 104 ) or mesenchymal stem cells derived from BM ( 105 ) or adipose tissue ( 106 – 108 ) ( Figure 1 ). In addition to pilot and proof-of-concept clinical studies, a significant proportion of published trials may be categorized as phase II RCT ( 100 , 101 , 109 – 111 ).…”

Non-pharmacological Treatment of Refractory Angina and Microvascular Angina

“…Trans-endocardial delivery of another autologous bone marrow-derived cells, CD133+ cells, were proved to be safe and feasible in two small phase I randomized trials not powered for efficacy end-points [82,83]. Another recent phase I randomized trial of intramyocardial injection of CD133+ cells in RA patient subset with LV dysfunction (LV < 45%) confirmed the safety profile of the previous two trials and showed significant improvements in CCS angina class, myocardial perfusion and function assessed by single-photon emission computer tomography at 12 months [84]. Moreover, improvements in myocardial perfusion were positively correlated with the proangiogenic growth factors, hepatocyte growth factor and platelet-derived growth factor type bb, substances involved in neovascularization, endothelial and muscle cell growth [85,86].…”

Stem cell therapy for heart failure in the clinics: new perspectives in the era of precision medicine and artificial intelligence

“…A considerable number of recent clinical trials in stem cell therapy for HF have demonstrated its promise and substantially increased our understanding of the behaviors and working mechanisms of stem/progenitor cells in patients ( Table 1 ). ( Hamshere et al, 2015 ; Martino et al, 2015 ; Perin et al, 2015 ; Choudry et al, 2016 ; Noiseux et al, 2016 ; Patel et al, 2016 ; Bartolucci et al, 2017 ; Butler et al, 2017 ; Choudhury et al, 2017 ; Florea et al, 2017 ; Gwizdala et al, 2017 ; Hare et al, 2017 ; Steinhoff et al, 2017 ; Teerlink et al, 2017 ; Xiao et al, 2017 ; Bassetti et al, 2018 ; Vrtovec et al, 2018 ; Yau et al, 2019 ; Bolli et al, 2020 ; He et al, 2020 ; Makkar et al, 2020 ; Mathiasen et al, 2020 ; Ulus et al, 2020 ; Bolli et al, 2021 ; Qayyum et al, 2023a ; Qayyum et al, 2023b ; Perin et al, 2023 ) In the next phase of clinical stem cell research, it is critical to address the outcome discrepancy between preclinical and clinical studies and expand the scope of stem cell-based therapy to other forms of cardiomyopathy, such as chemotherapy- or arrhythmia-induced cardiomyopathy. Exploiting the power of AI/ML and computational tools will facilitate our understanding of the benefits and limitations of stem cell therapy and provide a systems perspective for properly applying stem cell therapeutics in the context of precision and personalized medicine.…”