Methods for detection and elimination of residual human embryonic stem cells in a differentiated cell product

Methods for detection and elimination of residual human embryonic stem cells in a differentiated cell product

Funding Type: 
Early Translational I
Grant Number: 
TR1-01215
Award Value: 
$5,405,397
Disease Focus: 
Diabetes
Collaborative Funder: 
Victoria, Australia
Stem Cell Use: 
Embryonic Stem Cell
Status: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

ViaCyte is developing a cell therapy for diabetes, which will have a tremendous clinical and societal impact as such a large number of people are afflicted with this disease. The therapy is a combination product comprised of pancreatic progenitor cells transplanted within a device, Encaptra™. A large supply of pancreatic progenitors can be produced with a cell manufacturing process that involves the directed differentiation of human embryonic stem cells (hESC). After transplantation the pancreatic progenitor cells differentiate into functional islets that contain insulin-producing beta cells. Encaptra™ is designed to allow the release of insulin to regulate blood glucose levels while simultaneously protecting the transplanted cells from destruction by the patients’ immune system. The combined product provides a large assurance of safety since cells will be contained and the device is retrievable. This award is focused on product safety, principally the issue of tumorigenicity. Tumor formation is a particular consideration when using hESCs as cell manufacturing starting material since undifferentiated hESCs form a particular type of tumor, called a teratoma, when transplanted into animal models. Therefore, it is important to demonstrate that at the end of the manufacturing process the cell product is largely devoid of undifferentiated hESC and lacks teratoma potential. ViaCyte has been investigating and establishing standardized assays to measure the presence of hESCs and the potential for teratoma formation. In addition, ViaCyte has previously identified several compounds that appear to preferentially kill undifferentiated hESCs while not affecting the viability of pancreatic progenitors. To ensure that Encaptra™ will be fully effective in containing implanted cells in a patient, ViaCyte is developing various assays to ensure the quality of manufactured devices. These newly developed assays will be incorporated into the manufacturing process and data required by the FDA for product safety will be collected. Successful completion of this project will represent a major advance for stem cell-derived therapies and will specifically contribute to establishing a cell therapy for diabetes.

Year 2

ViaCyte is a preclinical company developing a stem cell-based therapy for insulin-dependent diabetes. The therapy is a combination product comprised of pancreatic progenitor cells, pro-islet, encapsulated within a retrievable delivery ENCAPTRA device. After implantation, encapsulated pro-islet differentiates into glucose-responsive, insulin-secreting cells that can regulate normal blood sugar levels in animal models of diabetes. The renewable starting material for pro-islet manufacturing is human embryonic stem cells (hESC) that are directed to differentiate to pancreatic cell product using scalable processes. The bio-stable ENCAPTRA device is designed to fully contain cells and to protect cells from immune attack. The goal is to develop a product that will achieve insulin independence, reduce diabetes-related complications, and eliminate the need for continuous immunosuppressant drugs. This CIRM award is focused on product safety. A large assurance of safety is provided by confining the transplanted cells within the device and by the ability to retrieve the product. Nonetheless, an important preclinical safety assessment of this combination product therapy is the evaluation of its tumorigenicity, i.e. its capacity to form tumors. Upon transplantation into animal models, undifferentiated hESC can generate a teratoma, a tumor that is akin to a particular type of germ cell tumor that can form in humans. There is a possibility that residual, undifferentiated hESC could remain in pro-islet, potentially giving rise to a teratoma. It is unclear whether teratomas can form when undifferentiated hESC are transplanted within ENCAPTRA and if so, what threshold dose of hESC in pro-islet could generate a teratoma. ViaCyte has been investigating and establishing standardized assays to measure the presence of hESC in pro-islet and the potential for teratoma formation. Preliminary tumorigenicity studies of pro-islet were completed with safe outcomes. With these data in hand, formal definitive tumorigenicity studies can be designed and initiated to include in a package to submit to the FDA as ViaCyte seeks approval to test the product in humans. To demonstrate that ENCAPTRA will be effective in containing implanted cells in a patient, ViaCyte is also developing assays to ensure the quality of manufactured devices. These newly developed assays are being incorporated into the cell manufacturing and device manufacturing processes, and data will be collected to show that the product is safe. Successful completion of the objectives of this award will help establish the safety of the product so that clinical trials can be initiated with the goal of developing a game-changing cell therapy for diabetes.

Year 3

ViaCyte is a company developing a stem cell-based therapy for diabetes. The therapy is a combination product, called VC-01™, comprised of human embryonic stem cell (hESC)-derived pancreatic beta cell precursors (PEC-01™ cell product), encapsulated within the Encaptra® drug delivery system (ENCAPTRA device). After implantation, the precursor cells mature into endocrine cells that secrete insulin and other hormones in a regulated manner to control blood sugar levels in animal models of diabetes. hESC are the renewable starting material for cell manufacturing; they are directed to differentiate to PEC-01 cell product using scalable processes. The retrievable ENCAPTRA device is designed to contain cells and to protect cells from immune attack. The goal is to develop a product that will provide insulin independence, reduce diabetes-related complications, and eliminate the need for chronic immunosuppressant drugs. This CIRM award is focused on product safety. An important nonclinical safety assessment of this combination product therapy is the evaluation of its tumorigenicity, i.e., its capacity to form tumors. Upon transplantation into animal models, undifferentiated hESC can generate a teratoma, a tumor that is akin to a particular type of germ cell tumor that can form in humans. Accordingly, to the extent that undifferentiated hESC could potentially remain in the differentiated PEC-01 cell product, these could potentially give rise to a teratoma. Prior to this award, it was unclear whether teratomas will form when undifferentiated hESC are implanted within the ENCAPTRA device and if so, what threshold dose of hESC in PEC-01 would be required to produce a teratoma. ViaCyte received this award to develop methods to assess teratoma potential with in vivo and in vitro assays, and to mitigate potential tumorigenicity risk by ensuring integrity of the encapsulation delivery device. ViaCyte has investigated a standardized assay to measure the presence of hESC in PEC-01 cell product, and preliminary tumorigenicity studies of VC-01 were completed with safe outcomes. With these data in hand, definitive IND-enabling tumorigenicity studies were designed and initiated to include in a package that will be submitted to the FDA as ViaCyte seeks approval to test the product in human clinical trials. A large assurance of safety is provided by confining the transplanted cells within the device and by the ability to retrieve the product. To demonstrate that the ENCAPTRA device will be effective in containing implanted cells in a patient, ViaCyte has also developed assays and performed studies to ensure the integrity of the ENCAPTRA device. Collectively, the data from these studies will form a compelling package to demonstrate the safety of the VC-01 product so that clinical trials can be initiated with the goal of developing a game-changing cell therapy for diabetes.

Year 4

ViaCyte is a company developing a stem cell-based therapy for diabetes. The therapy is a combination product, called VC-01™, comprised of human embryonic stem cell (hESC)-derived pancreatic beta cell precursors (PEC-01™ cell product), encapsulated within the Encaptra® drug delivery system (ENCAPTRA device). After implantation, the precursor cells mature into endocrine cells that secrete insulin and other hormones in a regulated manner to control blood sugar levels in animal models of diabetes. hESC are the renewable starting material for cell manufacturing; they are directed to differentiate to PEC-01 cell product using scalable processes. The retrievable ENCAPTRA device is designed to contain cells and to protect cells from immune attack. The goal is to develop a product that will provide insulin independence, reduce diabetes-related complications, and eliminate the need for chronic immunosuppressant drugs. This CIRM award is focused on product safety. An important nonclinical safety assessment of this combination product therapy is the evaluation of its tumorigenicity, i.e., its capacity to form tumors. Upon transplantation into animal models, undifferentiated hESC can generate a teratoma, a tumor that is akin to a particular type of germ cell tumor that can form in humans. Accordingly, to the extent that undifferentiated hESC could potentially remain in the differentiated PEC-01 cell product, these could potentially give rise to a teratoma. Prior to this award, it was unclear whether teratomas will form when undifferentiated hESC are implanted within the ENCAPTRA device and if so, what threshold dose of hESC in PEC-01 would be required to produce a teratoma. ViaCyte received this award to develop methods to assess teratoma potential with in vivo and in vitro assays, and to mitigate potential tumorigenicity risk by ensuring integrity of the encapsulation delivery device. ViaCyte has investigated a standardized assay to measure the presence of hESC in PEC-01 cell product, and preliminary tumorigenicity studies of VC-01 were completed with safe outcomes. With these data in hand, definitive IND-enabling tumorigenicity studies were designed and initiated to include in a package that will be submitted to the FDA as ViaCyte seeks approval to test the product in human clinical trials. A large assurance of safety is provided by confining the transplanted cells within the device and by the ability to retrieve the product. To demonstrate that the ENCAPTRA device will be effective in containing implanted cells in a patient, ViaCyte has also developed assays and performed studies to ensure the integrity of the ENCAPTRA device. Collectively, the data from these studies will form a compelling package to demonstrate the safety of the VC-01 product so that clinical trials can be initiated with the goal of developing a game-changing cell therapy for diabetes.

© 2013 California Institute for Regenerative Medicine