Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial

Patel, Amit N.; Henry, Timothy D.; Quyyumi, Arshed A.; Schaer, Gary L.; Anderson, R. David; Toma, Catalin; East, Cara; Remmers, Ann E.; Goodrich, James; Desai, Akshay S.; Recker, David P.; DeMaria, Anthony N.

doi:10.1016/s0140-6736(16)30137-4

Cited by 135 publications

(87 citation statements)

References 24 publications

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“…In parallel to this association between stem cells and macrophages, a recent clinical trial expanded bone marrow-derived MSCs and activated macrophages (CD45 + CD14 + autofluorescent + ) ex vivo (Ixmyelocel-T) for subsequent intramyocardial injection in patients with chronic ischemic dilated cardiomyopathy. 63 This combined cell therapy produced significant improvement in their primary end point (all-cause mortality, cardiac admissions, and HF admissions) and a modest improvement in LV function. It remains to be determined how the interaction between macrophages and stem cell-based therapies operates mechanistically and if therapy reduces systemic or local inflammatory processes that drive inflammation.…”

Section: Stem Cell Therapy In Chronic Hf: An Immunomodulatory Mechanismmentioning

confidence: 97%

Chronic Heart Failure and Inflammation

2016

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As a greater proportion of patients survive their initial cardiac insult, medical systems worldwide are being faced with an ever-growing need to understand the mechanisms behind the pathogenesis of chronic heart failure (HF). There is a wealth of information about the role of inflammatory cells and pathways during acute injury and the reparative processes that are subsequently activated. We discuss the different causes that lead to chronic HF development and how the sum of initial inflammatory and reparative responses only sets the trajectory for disease progression. Unfortunately, comparatively little is known about the contribution of the immune system once the trajectory has been set, and chronic HF has been established—which clinically represents the majority of patients. It is known that chronic HF is associated with circulating inflammatory cytokines that can predict clinical outcomes, yet the causative role inflammation plays in disease progression is not well defined, and the majority of clinical trials that target aspects of inflammation in patients with chronic HF have largely been negative. This review will present what is currently known about inflammation in chronic HF in both humans and animal models as a means to highlight the gap in our knowledge base that requires further examination.

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Section: Stem Cell Therapy In Chronic Hf: An Immunomodulatory Mechanismmentioning

confidence: 97%

Chronic Heart Failure and Inflammation

2016

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“…The expansion and co-culture process is believed to promote an M2-like phenotype in the macrophages, as demonstrated by expression of the cell surface markers CD206, CD163, and MerTK, and reduced secretion of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) even after stimulation with pro-inflammatory endotoxin [55]. In a phase 2B clinical trial of 125 patients treated for dilated cardiomyopathy (ischemic heart failure), transendocardial administration of ixmyelocel-T led to a 37% reduction in adverse cardiac events compared with the placebo group over 12 months of follow up [53]. By contrast, intramyocardial delivery of non-expanded autologous bone marrow mononuclear cells failed to show clinical improvement in a separate study of patients treated for ischemic cardiomypathy [56], although the two treatments have not been directly compared in the same study.…”

Section: Macrophage-based Therapies In Regenerative Medicinementioning

confidence: 99%

Macrophage-based therapeutic strategies in regenerative medicine

Spiller

Koh

2017

Advanced Drug Delivery Reviews

236

180

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Mounting evidence suggests that therapeutic cell and drug delivery strategies designed to actively harness the regenerative potential of the inflammatory response have great potential in regenerative medicine. In particular, macrophages have emerged as a primary target because of their critical roles in regulating multiple phases of tissue repair through their unique ability to rapidly shift phenotypes. Herein, we review macrophage-based therapies, focusing on the translational potential for cell delivery of ex vivo-activated macrophages and delivery of molecules and biomaterials to modulate accumulation and phenotype of endogenous macrophages. We also review current obstacles to progress in translating basic findings to therapeutic applications, including the need for improved understanding of context-dependent macrophage functions and the myriad factors that regulate macrophage phenotype; potential species-specific differences (e.g. humans versus mice); quality control issues; and the lack of standardized procedures and nomenclature for characterizing macrophages. Looking forward, the inherent plasticity of macrophages represents a daunting challenge for harnessing these cells in regenerative medicine therapies but also great opportunity for improving patient outcomes in a variety of pathological conditions.

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“…For example, the IxCell-DCM was a double-blind, placebo-controlled trial, which demonstrated a significant reduction in the primary end point using clinical events (death and cardiac hospitalization) in patients with class 3/4 ischemic heart failure. 20 In contrast to comments in the recent anonymous editorial, 1 from our perspective, the scientific pathway toward FDA approval of CD34 + cells for refractory angina was indeed "well-informed, disciplined progress toward the generation of data that satisfy the conditions of the regulatory agency." Indeed, the negotiation of a Special Protocol Assessment with the FDA attests to this fact.…”

Section: Cell Therapy Criticismmentioning

confidence: 91%