An engineered biomarker system to monitor and modulate immune clearance of cell therapies

Abstract

Cell transplants offer a new opportunity to deliver therapies with novel and complex mechanisms of action. Understanding the pharmacology of cell transplants is important to deliver this new therapy effectively. Currently, however, there are limited techniques to easily track cells after intravenous administration due to the dispersion of the graft throughout the entire body. We herein developed an engineered cell system that secretes a luciferase enzyme to sensitively detect cell transplants independent of their locale by a simple blood test. We specifically studied a unique feature of cell transplant pharmacology, namely immune clearance, using mesenchymal stromal cells (MSCs) as a proof of concept cell therapy. MSCs are a clinically relevant cell therapy that have been explored in several disease indications due to their innate properties of altering an immune response. Using this engineered reporter, we observed specific sensitivity of cell therapy exposure to the preparation of cells, cytolysis of MSCs in an allogeneic setting, and a NK cell-mediated destruction of MSCs in an autologous setting. Our cellular tracking method has broader implications at large for assessing in vivo kinetics of various other cell therapies.

Ex vivo perfusion-based engraftment of genetically engineered cell sensors into transplantable organs

“…Biosensor cells were added to perfusate to circulate and engraft in liver, and fresh perfusate without cells was swapped in after 180 minutes to test for engraftment. gLuc has been used as a highly sensitive reporter for assessment of cells in vivo , so levels in the perfusate allow us to track its activity within the rat livers [18, 19, 21]. There was a consistent pattern of gLuc secretion: an initial buildup in the first three hours, then a drop at the time of switching to fresh perfusate, and resumption of increase during hours 4–6.…”

“…The scope of this initial work was therefore to establish the integrity of biosensor cells infused into an organ using a constitutive CMV promoter to drive the secretion of Gaussia luciferase (gLuc), a bioluminescent biomarker probe [17]. We have previously investigated the pharmacokinetics of a cell therapy coupled with gLuc monitoring of cellular transplant [18] and used this technique to confirm immune clearance of such biomarker-secreting cells [19]. Furthermore, we tested the ability of a previously established ex vivo liver perfusion system [20] as a novel and enabling platform for engrafting cell biosensors into the organs prior to transplant.…”

Turning stem cells homing potential into cancer specific drug delivery machines

“…The safety of the MSC administration was mainly assessed based on the influence on surgery and recovery after surgery. Although the clearance of systemically administered MSCs is within 24 hours both in animal models and humans (11), the differentiation of uncleared MSCs by the liver presents a significant risk in systemically administered MSCs. The patients in the study by Schweizer et al 2019 were not reported have any problems with MSC administration in 30 days.…”