Immune Reprogramming in Human Subjects after Extracorporeal Mesenchymal Stromal Cell Therapy

Abstract

Background & Aim Mesenchymal stromal cells (MSCs) are a unique source of secreted factors that modulate an inflammatory response and enhance the repair of injured tissue. Sentien has created a novel delivery approach to enable sustained exposure to MSCs and their secreted factors, overcoming limits of cell transplantation/infusion while preserving the broad acting and dynamically responsive properties. Our lead product, SBI-101, contains allogeneic human MSCs inoculated into a hollow-fiber hemofilter, which promotes contact with patient blood via the semi-permeable membrane, while promoting MSC viability. SBI-101 is designed to restore balance to the immune system by reprograming the molecular and cellular components of blood in patients with severe organ injury. We are conducting a Phase I/II clinical study of SBI-101 in critically ill patients with Dialysis-Requiring Acute Kidney Injury (AKI-D). Methods, Results & Conclusion In the initial cohort analyzed, patients were randomized to receive SBI-101 (250 × 106 cells) or sham control up to 24 hours of treatment (n=4 per group). Over 200 exploratory biomarkers were measured to characterize the MSC response as well as the pharmacodynamic (PD) effects of SBI-101. Samples were collected for the measurement of immune cell populations, kidney injury biomarkers, and biomarkers of inflammation at pre dose, conclusion of treatment, days 1, 3, 7, 14, 21, and 28 post-treatment with SBI-101 or sham control. Data showed an MSC response that seems to be dynamic and specific to each patient. Trends in PD response were also observed. Inflammatory (anti- and pro-) markers, such as IL-10 and TNFa, consistent with MSC biology were shown to be modulated, suggestive of a shift from a pro- to anti- inflammatory state. In addition, innate and adaptive cellular immune changes were also observed, such as reduction in total monocytes. Finally, early markers of kidney injury (eg, KIM-1) were also seen to have effect sizes greater than one. Despite therapy being administered for a maximum of 24 hours, a durable effect was observed out to a week in some cases. While the study was not powered for significance, the results demonstrate a dynamic biological response from the MSCs with potentially beneficial effects in the immune system as well as in the kidney of these critically ill patients. Moreover, it supports the therapeutic hypothesis of SBI-101 as a potent immunotherapy.