A Novel CAR T Therapy for Selective Depletion of Autoimmune B cell in Lupus

A Novel CAR T Therapy for Selective Depletion of Autoimmune B cell in Lupus 

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown significant promise in clinical trials for individuals with severe lupus. This process involves reengineering a patient’s own T cells to target CD19, a marker on the surface of B cells. However, one downside to this approach is that targeting all B cells, including protective populations (B cells that defend against harmful invaders), can leave the individual immunocompromised. Dr. Bhoj will develop a novel CAR T cell that specifically targets self-reactive B cells (those that recognize a patient’s own body), allowing for effective cell therapy with minimal side effects. 

Dr. Bhoj will target age-associated B cells (ABCs), B cells that accumulate with age and are a major B cell driver of lupus. He will construct an innovative system (called CART-ABCs) in the lab in both human and mouse cells. He will then test the CART-ABCs in a mouse model of lupus, laying the groundwork for future testing in clinical trials. 

What this means for people with lupus 

By selectively targeting diseased-causing B cells and leaving protective B cells intact, Dr. Bhoj’s new platform could provide a safe, effective, and potentially curative therapy for individuals with lupus.

B cells play a central role in systemic lupus erythematosus (SLE). Recent clinical studies suggest that B-cell targeted chimeric antigen receptor (CAR) T cells can effectively deplete autoimmune B cells and induce disease remissions where traditional therapies have failed. A drawback of this approach is that all B cells, both pathogenic and protective B cells, are deeply depleted, leaving recipients immunocompromised. Thus, an approach that selectively targets pathogenic B cells would be optimal. A B cell subset known as age-associated B cells (ABCs), likely the major B cells drivers of disease in SLE, represents an attractive therapeutic target. Thus, we hypothesize that CAR T cells selectively targeting ABCs will effectively eliminate autoantibodies and ameliorate pathologic effects of lupus, with minimal off target immune suppression. We will develop an ABC-targeted CAR T cell platform (CART-ABC) in murine (Aim 1a) and human (Aim 1b) systems. While a validated human CART-ABC can be directly advanced to clinical evaluation, murine CARTABCs will enable preclinical studies that test efficacy, safety, and optimal dosing regimens to inform clinical application.

Aim 1. Develop a combinatorial dual-CAR platform to specifically deplete ABC and ameliorate lupus. There is no unique target marker on ABCs. However, among B cells, all of which express CD19, ABCs uniquely express CD11c. Since CD11c is also expressed on other immune cells, targeting CD11c with conventional CAR T cells would result in undesirable off-target effects. We hypothesize that a logic-gated strategy that only targets cells bearing CD19 AND CD11c would be specific to ABCs. In Aim 1a, we will construct a murine AND-gated CAR system targeting CD19 and CD11c (CART-ABC) and evaluate its efficacy and specificity in vitro and in vivo using the Bm12 cGVHD murine lupus model. In Aim 1b, we will develop the CART-ABC platform for use in humans. We will use phage display to isolate antibodies to human CD11c which we will use to construct conventional CD11c CARs. After evaluation of CD11c CAR candidates, 1-2 will be used to build the CART-ABC platform along with existing CD19 binders. The platform will be optimized for specific target cell depletion in vitro using engineered target cell lines as well as in vitro generated human ABCs. If successful, results of these and future in vivo studies including in humanized mouse models will support an IND application enabling clinical testing.

Our proposal builds on recent exciting data using B cell ablative CD19 CAR T cells for treatment of refractory SLE. Our CART-ABC platform would significantly enhance the approach by depleting pathogenic B cells while preserving beneficial memory and naïve B cells, providing an effective and safe therapy for patients with lupus. Additionally, the platform may also be applicable for autoimmune diseases beyond SLE, where ABCs have been implicated.