A Novel CART Cell Selectively Targeting Age-Associated B Cells to Treat Lupus

A novel CART cell selectively targeting age-associated B cells to treat lupus 

Systemic lupus erythematosus (SLE) is a disease driven by B cells, immune cells that produce antibodies to protect against infections, but in SLE, they produce autoantibodies that mistakenly target the body’s own cells and tissues, leading to inflammation. In mouse models, eliminating B cells has successfully treated the disease. However, in humans, treatments such as rituximab have not met clinical expectations, likely due to incomplete B cell depletion. Recent studies have shown that CD19-targeted chimeric antigen receptor (CAR) T cells, which are engineered to recognize and eliminate CD19+ B cells (B cells that express the CD19 protein on their surface), can effectively treat lupus in both mouse models and humans with severe disease. This has opened up new therapeutic opportunities, but current approaches target all B cells, including those that are beneficial, leading to immunodeficiency and increased risk of infections. Dr. Shlomchik aims to develop a more targeted therapy that focuses on eliminating only the harmful B cells. 

One promising target is the age-associated B cell (ABC), also known as double-negative (DN)2 B cells in humans. These cells are highly correlated with disease severity in lupus. Dr. Shlomchik proposes to develop a novel CAR T cell, called CAR1911, which will be activated only when it recognizes both CD19 and CD11c, which is expressed on ABCs. This selective approach aims to eliminate only the disease-causing B cell subsets while sparing the protective ones. He will first validate these CAR1911 T cells in the lab and then test their effectiveness in mouse models. If successful, this approach could provide a powerful pre-clinical rationale for translating this novel CAR T cell therapy to treat lupus and other autoimmune diseases. 

What this means for people with lupus 

Dr. Shlomchik’s research could lead to a more precise and safer CAR T cell therapy for lupus, targeting only the harmful B cells and reducing the risk of immunodeficiency. This could significantly improve treatment outcomes and quality of life for individuals with lupus. 

SLE is a B cell-driven disease. In murine models, genetic elimination of B cells eliminated disease. Disappointingly, in humans, Rituximab and similar drugs did not meet clinical endpoints when given in standard regimens, likely due to incomplete depletion. Kansal et al. demonstrated in the MRL/lpr mouse model that CAR19 T cells, which are engineered to display a chimeric antigen receptor that recognizes CD19, effectively deplete B cells and can treat lupus even in this robust animal model. To great excitement, recent (albeit anecdotal) studies show that in SLE patients CAR19 T cells also deplete B cells and treat even severe disease. This finding has opened up new therapeutic opportunities, including CAR19 T cells, bi-specific T cell-engagers, and more potent anti-CD20 Abs. However, these approaches target all B cells, including the entire naïve B cell bystander population as well as memory B cells that are specific for important pathogens. This in turn can lead to substantial immunodeficiency, inability to respond to vaccines, and opportunistic infections. It would be more ideal to target pathogenic subsets of B cells. One such subset has emerged as a leading candidate: the “age-associated B cell” or ABC. Termed “DN2 B cells” in humans, because they lack the memory B cell marker CD27 as well as IgD, these cells in both mice and humans express CD11c and the transcription factors Tbet and Zeb2. ABCs are highly correlated with disease severity in lupus. We recently showed that a genetic approach to deleting ABCs in the MRL/lpr model reduced disease, providing strong rationale for further study. Here we propose to develop a novel CART cell that will be triggered to kill only upon recognition of both CD19 AND CD11c, dubbed “CAR1911”. This CART, and other variants of it, described in the full proposal, would enable the selective elimination of ABC and/or other pathogenic B cell subsets. We will first validate these CART cells in vitro and then use them to treat lupus in MRL/lpr mice, analogous to Kansal et al. In parallel, we will develop human-specific CART cells and demonstrate their efficacy in vitro. Together, if successful, these efforts should provide a powerful pre-clinical rationale for the translation of a novel CART approach to treat lupus and allied autoimmune diseases. Specifically, we propose the following three Aims: 1) Design and express the CAR1911 chimeric antigen receptor in both murine and human formats; 2)Validate the killing efficiency and specificity of CAR1911 T cells on relevant target cells and populations in vitro; 3) Generate CAR1911 T cells from MRL/lpr mice, determine a dose-response curve for in vivo ABC depletion in mice with moderate disease, then apply this dosing strategy to a disease cohort to determine if lupus-like disease will be ameliorated. Success will provide both mechanistic insights into SLE and a novel and precise therapy for lupus patients.