Patients with end-stage heart failure (ESHF) have a 2-year survival rate of 50% with conventional medical therapy. We propose to evaluate a new cell therapy approach (human embryonic stem cell-derived cardiomyocytes; hESC-CMs) to improve survival and cardiac function in these patients. The proposed cell product is generated from the federally approved human embryonic stem cell (hESC) line WA07; the hESC-CMs are then produced in a good manufacturing practice (GMP)-compliant process at City of Hope. The hESC-CMs are cryopreserved at harvest and thawed for subsequent immediate use. The overall dose of hESC-CMs in our phase 1 safety clinical trial is expected to be between 100 million and 300 million cells; the percentage of cardiomyocytes in the cell product is ≥ 80%, as assessed by flow cytometry for cardiomyocyte-specific protein expression.
The population for this study will be a subgroup of ESHF patients: those undergoing left ventricular assist device (LVAD) implantation, either as a bridge toward orthotopic heart transplantation (OHT) for refractory heart failure or as destination therapy when patients are not eligible for transplant or appropriate donor hearts are unavailable. Clinical assessment of improved function will be assessed by temporary “LVAD weaning”, in which the pump speed of the device is turned down to minimal levels and the patient’s cardiac function is assessed by both echocardiography and the 6 minute walk test. Accordingly, it is possible to assess the effects of therapies without putting the patient at serious risk.
Due to the allogeneic nature of the H7 hESC-CMs, patients will undergo low-dose temporary immunosuppression (starting on the day of LVAD implantation/hESC-CM injection; 2 weeks in duration). We do not anticipate long-term survival of transplanted cells, which is the current norm in the cardiac stem cell field. We do anticipate that the injected cells will release angiogenic factors that act upon the native myocardium, resulting in improved function. This biological mechanism has been well described in numerous other pre-clinical studies as well as clinical trials, whereby the injected stem cells do not persist long-term in the heart but still provide functional benefits.
In order to demonstrate the feasibility and safety of this approach, we have performed studies over the past year showing that a) animals that received transplants of the hESC-CMs show no evidence of any tumors after more than 6 months; b) the hESC-CMs improve heart function in a rodent model of heart disease; and c) delivery of the full human dose of hESC-CMs into a large animal model of heart failure (immunosuppressed pigs) shows no evidence of increased risk of dangerous arrhythmias or other adverse effects. We are in the process of evaluating any improvements in cardiac function in this large animal model of heart disease as well; due to the extreme difficulty of preventing rapid rejection of human cells in these animals, we do not necessarily anticipate seeing the same changes in function we expect to see in patients, where the cells should survive longer. We have met with FDA to help us design our crucial preclinical studies, if results show the hESC-CMs are safe and efficacious, we will use this data to gain approval to go forward with a proposed clinical trial.