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In clinical trials, CD19-targeted chimeric antigen receptor (CAR) T cell therapy, which involves reengineering a patient’s own T cells to target and eliminate CD19+ B cells (which play a crucial role in the autoimmune response in lupus), has shown promising success in treating individuals with severe lupus. However, high costs, limited access to necessary medical procedures, and lengthy manufacturing times are significant barriers preventing CAR T cells from being more widely used. Additionally, patients must reduce certain medications, including immunosuppressants and steroids, prior to CAR T cell therapy. This poses a key obstacle to many patients, especially those at higher risk of flares. Dr. Benjamin and Dr Wincup are testing a novel method that involves only a single blood draw and an optimized CAR design, aiming to make the process more streamlined, less expensive, and more accessible. 

Dr John Maher at Kings College London developed a next-generation CAR system, called parallel CD19-directed CAR T product (pCAR19), which more effectively targets disease-causing cells.  Dr Benjamin and Dr Wincup will test the safety and efficacy of pCAR19 in cells from 25 people with active lupus. Utilizing the Cocoon® system, which can produce CAR T cells in as few as three days, they aim to overcome current manufacturing delays that limit timely treatment for severely ill patients. Additionally, the impact of immunosuppressive and glucocorticoid therapy on the production of pCAR 19 cells will be investigated. If potent and safe CAR T cells can be generated from a patient without tapering current medications, this could revolutionize treatment options for those with severe disease. 

What this means for people with lupus

While a transformative treatment, CAR T cell therapy is not widely used due to several key barriers. The work of Dr. Benjamin and Dr Wincup could drastically reduce logistical barriers and costs, allowing a wider population of people with lupus to benefit from this promising therapy. 

Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising approach for treating Systemic Lupus Erythematosus (SLE), with early studies showing success in inducing remission in patients with limited treatment options. However, widespread adoption faces a number of challenges, including high costs, limited access to apheresis, lengthy manufacturing processes, and the need to taper concurrent immunosuppressive / glucocorticoid therapies in patients with severe disease. Additionally, variability in T cell subpopulations, function, and metabolism before and after CAR transduction remains poorly understood and hindering treatment optimization as these may be factors that impact on response.

This proposal aims to address these challenges by developing a faster, more accessible, and predictable CAR T cell therapy for SLE. We propose a novel rapid manufacturing process that involves a single peripheral blood draw, eliminating the need for apheresis, thus reducing costs and logistical barriers. Our approach focuses on a next-generation CAR construct (pCAR19) with an affinity optimized antigen-binding domain and dual CD28 and 4-1BB costimulation. By leveraging the Lonza Cocoon® system, we aim to produce CAR T cells in as little as three days, overcoming the manufacturing delays that currently limit timely treatment for acutely ill patients. This rapid production from a small blood sample could make CAR T cell therapy more accessible to a larger population.

We will evaluate the efficacy and safety of pCAR19 generated from peripheral T cells of 25 patients with active SLE (SLEDAI-2K =6 or BILAG 1A/2B). Flow cytometry will be used to quantify key T cell subpopulations. We will assess B cell cytotoxicity, the elimination of SLE-related autoantibodies, and changes in cellular metabolism following pCAR19 transduction via already established techniques. A key focus will be on optimizing T cell metabolism to enhance efficacy while minimizing proinflammatory cytokine production, a critical safety consideration.

Furthermore, we will investigate the impact of concurrent immunosuppressive and glucocorticoid therapy on the generation of safe and effective pCAR19 cells. Current protocols often require tapering these therapies before T cell collection, which can be risky for patients with highly active disease. By including patients on higher levels of background therapy, we aim to determine if enforced tapering is necessary, potentially leading to safer and more inclusive treatment protocols.

In conclusion, this study seeks to generate preclinical evidence to support an early-phase clinical trial of this novel manufacturing process and CAR T cell construct. By demonstrating that rapidly produced, potent, and safe CAR T cells can be generated from a single blood draw without requiring significant therapy tapering, we aim to revolutionize treatment options for patients with severe SLE, expanding access to this highly effective therapy.