OX40L Targeted Chimeric Antigen Receptor (CAR) Tregs for SLE

Systemic lupus erythematosus (SLE) is a complex and challenging disease that requires lifelong immune suppression. Many current treatments are not completely effective and can cause harmful side effects, highlighting the critical need for curative therapies. Cellular therapies, particularly regulatory T cells (Tregs), offer a promising approach. Tregs promote immune tolerance (the body’s ability to prevent an immune response to the body’s own tissues) through various mechanisms and have shown an excellent safety profile in Phase 1 studies for other diseases, without the need for lymphodepletion, a chemotherapy treatment typically needed prior to CAR T cell administration. To enhance their potency, Tregs can be engineered with chimeric antigen receptors (CAR-Tregs) to target specific proteins. Dr. Kean has developed a CAR-Treg platform that targets OX40 ligand (OX40L), a protein on activated antigen-presenting cells (APCs) that stimulates harmful T cells in lupus.

Dr. Kean hypothesizes that CAR-Tregs can help restore balance to the immune system in people with lupus by targeting these specific immune cells. She will first test whether OX40L-CAR-Tregs have enhanced suppressive mechanisms compared to non-targeted Tregs in cell culture systems. In the second phase, Dr. Kean will test the efficacy of OX40L-CAR-Tregs compared to non-targeted Tregs in lupus-prone mice.

What this means for people with lupus

Dr. Kean’s research could lead to a potent CAR-Treg therapy for lupus, promoting immune tolerance and potentially achieving drug-free remission (absence of symptoms without requiring any other treatments). This innovative approach could significantly improve treatment outcomes and quality of life for individuals with lupus.

Systemic lupus erythematosus (SLE) is a complex and challenging disease, which is managed by life-long immune suppression. Given the multiple and cumulative toxicities of current treatments, there is a critical unmet need to develop curative therapies. Cellular therapies may represent such an approach. Of particular interest, are regulatory T cells (Tregs), which are cells that can promote immune tolerance by multiple mechanisms of action on diverse cell types. In phase I studies for other diseases, Treg therapies have an excellent safety profile and do not require any chemotherapy prior to administration. To enhance their potency, Tregs can be engineered to have chimeric antigen receptors (CAR-Tregs) to promote antigen-specific suppression. Because autoantigens are numerous and variable in patients with SLE, we have developed a CAR-Treg platform that does not target an individual autoantigen, but instead targets OX40L, a surface protein expressed on activated antigen presenting cells (APCs) that potentiates SLE by costimulating pathogenic T cells. Our central hypothesis is that by directing the regulatory actions of OX40L-CAR-Tregs towards activated APCs, these cells will break a crucial link between innate (APC) and adaptive (T cell) immune dysregulation in SLE, thereby promoting immune tolerance. In Aim 1, we focus on human OX40L-CAR-Tregs to determine the mechanisms by which they modulate known immune pathways in SLE. Using in vitro studies, we will test the hypothesis that OX40L-CAR-Tregs will have enhanced suppressive mechanisms towards APCs vs. control, non-targeted (NT)-Tregs. Specifically, we predict that there will not only be a greater total regulatory effect from more uniform activation of CAR-Tregs by OX40L-expressing APCs but also that CARTregs will have a unique mechanism of action – CAR-mediated removal of OX40L from APCs via trogocytosis, limiting the ability of APCs to provide costimulation to effector T cells. In Aim 2, we use in vivo models to compare immune regulation by murine OX40LCAR-Tregs and NT-Tregs in two complementary models of lupus-prone mice (NZBWF1/J, MRL-lpr). We will test the hypothesis that murine OX40L-CAR-Tregs will be therapeutically superior to NT-Tregs by enhancing Treg activation and persistence in diseaseaffected tissues, which we will determine using standard clinical and immunologic assessments as well as bioluminescence imaging to track Tregs in vivo. If successful, this project will advance the development of a potent, CAR-Treg therapy for SLE, which, by promoting immune tolerance in response to immune activation markers, has the potential to promote drug free remission.