Optimized CAR-T Therapy for Lupus

Lymphodepletion, a chemotherapy treatment that is usually needed before chimeric antigen receptor (CAR) T cell therapy, can cause overall immune suppression which can result in side effects such as infections. Dr. O’Neil is developing a new form of CD19 CAR T cell therapy that does not require lymphodepletion, potentially lowering the toxicity of this revolutionary therapy. Dr. O’Neil will assess the effectiveness of this new CAR-T cell therapy in depleting B cells, which are key drivers of lupus, without the need for lymphodepletion. He will compare the effectiveness of this new therapy to existing treatments such as Rituximab in a lupus mouse model.

In addition to evaluating the effectiveness of the new CAR-T cell therapy, Dr. O’Neil will investigate the kinetics of B cell depletion, which refers to the rate and extent to which B cells are eliminated from different tissues in response to the new CAR-T cell therapy. By monitoring B cell levels in the blood and various tissues, such as the spleen, lymph nodes, bone marrow, and kidneys, at different time points, the study aims to provide a comprehensive understanding of how the therapy works over time. Lastly, in collaboration with the clean cell manufacturing facility at MUSC, Dr. O’Neil aims to create and manufacture a highly purified CAR-T cell product that can be used in clinical trials for lupus.

What this means for people with lupus

Dr. O’Neil’s research could lead to a safer and more effective CAR-T cell therapy for lupus that does not require chemotherapy beforehand, making it more accessible and reducing the risk of side effects. Additionally, developing a scalable and validated manufacturing process could pave the way for broader clinical use, bringing this promising therapy closer to patients in need.

The studies proposed here will investigate the utility of a novel form of CD19 CAR-T cell therapy developed in our laboratory that does not require lymphodepletion. These studies will provide a unique opportunity to study the kinetics of B cell aplasia mediated by CAR-T therapy, which is normally confounded by the lymphodepletion. The studies described in Aim 1 are designed to define the nature, extent, tissue specificity of B cell subsets that are depleted within different tissues in response to CD19 directed CAR-T therapy and will be benchmarked against anti-CD20 Ig which is a mouse surrogate of Rituximab. Additionally, these studies will define the efficacy of CD19 CAR-T therapy administered without lymphodepletion in a pre-clinical SLE model. In Aim 2 we develop and optimize a scalable pipeline for generating and validating mRNA modified CD19 CAR-T cells from SLE patients. Importantly, we include an innovative manufacturing step and novel QC processes uniquely suited to functionally characterize mRNA modified CAR-T cells. These studies will enable an investigational new drug application for Stat5b* mRNA modified CD19 CAR-T cells for SLE. These studies will be conducted in collaboration with the FACT accredited clean cell facility at MUSC and leverage a unique and innovative manufacturing process resulting in a highly purified and metabolically fit CD19-CAR T cell product currently deployed a lymphoma trial at MUSC (NCT05702853).

Aim 1: Evaluate the B cell depletion kinetics and therapeutic efficacy of Stat5* mediated CD19 CAR-T therapy in the MRL/lpr SLE model. We will treat animals using effective CAR-T cell construct identified in Aim 1 in the context of this well-defined pre-clinical model of SLE. In addition to examining CAR-T cell trafficking and kinetics, we will monitor B cell aplasia over time in blood and evaluate B cells in tissue samples including spleen, lymph nodes, bone marrow, and Kidney at defined timepoints.

Aim 2: Develop a GMP compatible pipeline for manufacture and QC of mRNA modified autologous CD19 CAR-T cells from SLE patients. Optimization of manufacturing and validation of QC processes will be conducted using PBMCs collected from 6 SLE patients.