307.5: Modified Approach Allowed for Improved Islet Allotransplantation Into Pre-vascularized Sernova Cell PouchTM Device - Preliminary Results of the Phase I/II Clinical Trial at University of Chicago

Abstract

Introduction: After the first-in-human pilot study which showed safety of the pre-vascularized Sernova Cell Pouch (SCP) in the subcutaneous space, we modified islet transplantation (ITx) conditions for improved engraftment in the SCP. Methods: Two sets of the SCP were implanted in the abdominal anterior rectus sheath in seven patients with longstanding type 1 diabetes mellitus, problematic hypoglycemia and no stimulated C-peptide. Only highly purified islets were used for ITx and islets were suspended in the patient's own serum. Immunosuppression was initiated 1 month later followed by a marginal dose ITx after another month. Small sentinel SCPs were explanted for histopathological evaluation 3 months after each ITx. Results: Seven patients were submitted to 21 study related surgeries with a wound infection in 2 patients after SCP implantation with only one patient requiring device excision. The first subject presented with persistent stimulated serum C-peptide at 6 months after 1st and 2nd ITx into SCP. After 2nd ITx, glucose control improved substantially including reaching optimal target values for CGM with only 5% of Time Below Range (TBR). Subsequent intraportal ITx allowed for insulin independence currently maintained for over 15 months. The second patient at 3 months after 2nd ITx had positive stimulated serum C-peptide (0.48 ng/mL) with reduction of HbA1c from 10.6% to 7.6%, decreased insulin requirement from 49 to 28 u/day, improved CGM with TBR <4%, and reduction in Time Above Range (TAR) from 76% to 48%. To date, stimulated C-peptide has been detected for over 9 months. Three additional patients recently received ITx and await evaluation. Conclusion: Persistent islet graft function with sustained blood levels of C-peptide, reduction of HbA1c, improved CGM parameters, reduction of SHEs, and decreased total daily insulin requirement was achieved in the first 2 patients after ITx into SCPs implanted into abdominal wall. Significantly improved islet engraftment and clinical outcomes occurred using a modified approach for ITx into SCP.

Outcomes Following Extrahepatic and Intraportal Pancreatic Islet Transplantation: A Comparative Cohort Study

“…15,22,23 However, a recent oral presentation by Dr Witkowski's group suggests that the prevascularized subcutaneous space (using similar techniques to the one employed in this study) can achieve engraftment and sustained C-peptide production and insulin dose reduction in humans when a lower islet tissue concentration is transplanted in the subcutaneous device within the rectus muscle fascia. 39 Our experience here only includes 3 patients and it remains possible that our observed failure with subcutaneous ITx is due to device capacity overload from the high islet masses that we implanted. 23 Alternatively, improved vascularization within intramuscular sites may offer potential improvements to current techniques.…”

Cell delivery systems: Toward the next generation of cell therapies for type 1 diabetes

“…In July 2019, Sernova reported promising results from the first recipient with no major adverse events and the device being well vascularized 31 . Stimulated C‐peptide has been reported for up to 9 months in 2 recipients with a lowering of the level of glycated haemoglobin from 10.6% to 7.6% and a reduction in daily exogenous insulin from 49 U to 28 U 32 . Recognizing that it would be helpful if recipients did not have to be immunosuppressed, Sernova is now contemplating placing the ß cells in hydrogel capsules to protect them from the host immune system once they are introduced into the pre‐vascularized device.…”