Adoptive Approach to Cell-Supportive Therapy Based on Chimeric Receptors

Type 1 diabetes mellitus (T1DM) is an immune-mediated disease resulting in the damage and destruction of pancreatic β-cells and eventual complete loss of endogenous insulin supply. It predominately develops at a young age and accounts for 5-10 % of the diabetic population. Regardless of the advancements in diabetes therapeutics and technologies, the majority of the cohort with T1DM do not achieve recommended glycemic goals and remain at high risk of developing microvascular complications, such as neuropathy, nephropathy and, retinopathy.

In healthy individuals, the incretin effect is responsible for approximately 70% of insulin secretion. Preliminary results have shown a possible defect in the incretin effect in patients with T1DM. The incretin hormone, glucagon-like peptide (GLP)-1, has the potential to provide a therapeutic therapy affecting the underlying pathophysiology and improving glycemic control in T1DM. GLP-1 agonists may be beneficial in both longstanding and new onset T1DM patients by reducing the insulin requirements in longstanding T1DM and perhaps even delaying the absolute dependence upon insulin administration in new onset T1DM. One of the main limitations of GLP-1 agonists is their short biological half-life.

Our study focuses on employing chimeric receptors to generate primary T-cell cultures, overexpressing various GLP-1R-agonistic vectors, known as TRAMMICS cells, with the ability to bind to and activate pancreatic islet β-cells resulting in the release of insulin and expectantly the proliferation of the pancreatic β-cells. The advantages of using T-cells for this concept include, their long retention time in the body, their ability to penetrate various tissues when activated, possible increased receptor cross-linking efficiency compared to soluble ligands and less side effects owing to it being a more targeted system.

In order to test our hypothesis in-vitro we generated target and effector cell lines overexpressing the GLP-1R and various GLP-1R-agonistic vectors such as, α-GLP-1R or double exendin-4. To date, we have demonstrated our effector BW-TRAMMICS cells have the capability to activate the GLP-1R on various targets expressing the GLP-1R by the release of insulin and mouse IL-2. We have also shown that our target cell lines are able to activate the effector TRAMMICS cells upon interaction, shown by the secretion of mouse IL-2.