1743-P: Engineering Erythrocytes with the SQZ Cell Therapy Platform to Enhance Immunotolerance

Abstract

Current treatments for autoimmune disorders typically rely on the use of broadly immunosuppressive agents that increase the risk of adverse events in patients, such as cancer and opportunistic infections. Antigen (Ag)-specific immunotherapies have the potential to minimize these risks and improve efficacy by generating Ag-specific suppression to maintain immunohomeostasis. Several studies have established Ag-specific tolerance using red blood cells (RBCs) as a platform for delivery and Ag presentation in the context of eryptosis, a mechanism of RBC clearance. Here, we used the SQZ cell therapy platform to create Agloaded, pro-eryptotic RBCs to induce tolerance. In this approach, cells pass through constricted channels that cause transient permeation of the cell membrane and permit diffusion of cargo before the membrane reseals. In mice, we demonstrated that these highly delivered RBCs are rapidly cleared from circulation by splenic and liver-resident macrophages. The administration of ovalbumin (OVA)-SQZ’d RBCs led to a reduction of OVA-specific T cell proliferation and cytokine production in an OVA immunization model. In an autoimmune diabetes BDC2.5 T cell transfer model, mice treated with RBCs SQZ’d with 1040-p31 peptide mimetope delayed the onset of hyperglycemia in 80% of mice. Additionally, we developed mouse models for adenoassociated virus (AAV)-gene therapy and anti-drug antibody (ADA) to examine immunemediated clearance of exogenous Ag. In the AAV vector-specific model, mice treated with RBCs loaded with AAV-derived peptides abrogated the effector responses of AAV-specific CD8+ T cells upon restimulation. In a model of ADA responses, RBCs SQZ’d with a model drug also led to potent inhibition of ADA responses and preserved drug levels in circulation. In summary, SQZ’d RBCs are a potentially exciting allogeneic cell therapy strategy to induce Ag-specific tolerance across a range of disease mechanisms and indications. Disclosure A. Ramakrishnan: None. T. Lee: None. L.J. Moore: None. A. Vicente Suarez: None. F. Moore: None. H. Bernstein: Employee; Self; SQZ Biotechnologies. Funding JDRF