Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports.

Introduction: With the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies. Study design: The inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response. Results: In the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation. Conclusions: Our case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials.

Prognosis of Patients With Heart Failure Receiving Autologous Myoblast Patches　- Comparison of Single-Arm Trial Data to Registry Data.

BACKGROUND: Clinical studies in regenerative medicine remain insufficient in Japan due to ethical concerns regarding the control group and a lack of statistical methodology to evaluate efficacy in a small treatment group. This study evaluated the efficacy of autologous myoblast patch (AMP) treatment for heart failure using restricted mean survival time (RMST) analysis by comparing data from a small single-arm trial to epidemiological data from a registry.Methods and Results: The clinical trial arm included 55 patients with advanced ischemic cardiomyopathy who received an AMP between 2010 and 2020. The registry-based control group comprised 937 participants with severely impaired left ventricular function who were hospitalized for heart failure during the study period. Due to the limited number of patients, RMST analysis was used to compare survival between the 2 groups. Cox regression analyses revealed non-significant differences in survival between the groups at 3, 3.5, and 4 years. In contrast, RMST analyses revealed significant differences in survival at 3 years (P=0.008) and 3.5 (P=0.024) years, but not at 4 years. CONCLUSIONS: This small single-arm trial using RMST analyses was able to detect the efficacy of AMP transplantation for advanced heart failure (compared with a registry-based control group), with better survival until 3.5 years. This approach may be useful for efficacy analyses in regenerative medicine, where traditional clinical trials are difficult.

Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy.

Despite major therapeutic advances, heart failure, as a non-communicable disease, remains a life-threatening disorder, with 26 million patients worldwide, causing more deaths than cancer. Therefore, novel strategies for the treatment of heart failure continue to be an important clinical need. Based on preclinical studies, allogenic human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) patches have been proposed as a potential therapeutic candidate for heart failure. We report the implantation of allogeneic hiPSC-CM patches in a patient with ischemic cardiomyopathy (ClinicalTrials.gov, #jRCT2053190081). The patches were produced under clinical-grade conditions and displayed cardiogenic phenotypes and safety in vivo (severe immunodeficient mice) without any genetic mutations in cancer-related genes. The patches were then implanted via thoracotomy into the left ventricle epicardium of the patient under immunosuppressive agents. Positron emission tomography and computed tomography confirmed the potential efficacy and did not detect tumorigenesis in either the heart or other organs. The clinical symptoms improved 6 months after surgery, without any major adverse events, suggesting that the patches were well-tolerated. Furthermore, changes in the wall motion in the transplanted site were recovered, suggesting a favorable prognosis and the potential tolerance to exercise. This study is the first report of a successful transplant of hiPSC-CMs for severe ischemic cardiomyopathy.