同种异体间充质前体细胞治疗缺血性或非缺血性心力衰竭患者的 II 期剂量递增研究。

A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure.

机构信息

From the Stem Cell Center (E.C.P., G.V.S., Y.Z., J.T.W.), Adult Cardiology (E.C.P., G.V.S., J.T.W.), Texas Heart Institute, Houston; Borow Consulting Group, LLC, Bryn Mawr, PA (K.M.B.); Division of Cardiology, School of Medicine, University of California San Diego (A.N.D.M.); Heart and Vascular Institute, Center for Heart and Vascular Quality, Outcomes, and Clinical Research, University of Pittsburgh Medical Center, PA (O.C.M.); Heart and Vascular Institute, Swedish Medical Center, Seattle, WA (P.P.H.); Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, MN (J.H.T.); Monash University, Melbourne, Australia (H.K.); Mesoblast, Inc, New York (D.S.); Mesoblast, Inc, Melbourne, Victoria, Australia (S.I.); and Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.).

出版信息

Circ Res. 2015 Aug 28;117(6):576-84. doi: 10.1161/CIRCRESAHA.115.306332. Epub 2015 Jul 6.

DOI:10.1161/CIRCRESAHA.115.306332

PMID:26148930

Abstract

RATIONALE

Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF).

OBJECTIVE

To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial.

METHODS AND RESULTS

We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control).

CONCLUSIONS

Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

摘要

背景

同种异体间充质前体细胞（MPC）已在缺血性和非缺血性心力衰竭（HF）的大动物模型中显示出有效性。

目的

在 2 期临床试验中评估 3 种剂量（2500 万、7500 万或 1.5 亿个细胞）免疫选择的同种异体 MPC 在慢性 HF 患者中的可行性和安全性。

方法和结果

我们按顺序将 60 例患者分配到剂量组（每组 20 例），并将他们随机分为经心内膜 MPC 注射组（n=15）或模拟手术组（n=5）。主要终点是安全性，包括抗体检测。次要疗效终点包括主要不良心脏事件（MACE；心脏死亡、心肌梗死或血运重建）、左心室成像和其他临床事件替代指标。安全性和 MACE 评估时间最长达 3 年。MPC 注射是可行且安全的。各组的不良事件相似。未观察到有临床症状的免疫反应。15 例患者出现 MACE：MPC 治疗组 10 例（22%），对照组 5 例（33%）。我们发现 MPC 治疗组和对照组患者的生存率、MACE 无事件生存率和全因死亡率无差异。我们对 HF 相关 MACE（HF 住院、成功复苏的心脏死亡或心脏死亡）进行了事后分析，结果显示，1.5 亿 MPC 组（0/15）与对照组（5/15；33%）、2500 万 MPC 组（3/15；20%）和 7500 万 MPC 组（6/15；40%）相比，事件明显减少；根据 Kaplan-Meier 统计学，1.5 亿 MPC 组与所有组在 3 年以上时间差异有统计学意义（1.5 亿 MPC 组与对照组比较，P=0.025）。