Sensitive and Bispecific Chimeric TCR for SLE Therapy

Abnormal activation of B cells plays a crucial role in the development of systemic lupus erythematosus (SLE). While CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown significant benefits in treating SLE, it has several limitations. These include the inability to eliminate long-lived plasma cells that produce harmful antibodies, excessive production of inflammatory molecules called cytokines that cause toxicity, unpredictable recovery of the immune system, and the need for chemotherapy before treatment, which can have side effects. Dr. Riddell is developing a new therapeutic strategy using a synthetic chimeric T cell receptor (ChTCR) that targets both CD19+ B cells and BCMA+ plasma cells.

Dr. Riddell’s approach involves creating a bispecific ChTCR (Bi-ChTCR) that can simultaneously eliminate both harmful B cells and plasma cells. This new therapy aims to reduce the production of harmful antibodies and minimize side effects. The Bi-ChTCR will also include a safety switch that allows doctors to control the therapy and help the immune system recover. Dr. Riddell will compare the safety and effectiveness of this new therapy to existing CAR T cell therapies using a lupus mouse model that mimics the diversity of human immune cells and allows for long-term study. This research will provide valuable insights into the roles of B cells and plasma cells in SLE and advance new concepts in cellular therapy for autoimmune diseases.

What this means for people with lupus

Dr. Riddell’s research could lead to a safer and more effective therapy for lupus that targets both harmful B cells and plasma cells, reducing the risk of side effects and improving treatment outcomes. This innovative approach could significantly enhance the quality of life for people with lupus.

Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by the dysregulated activation of the adaptive immune system resulting in organ inflammation. Abnormal B-cell activation plays a crucial role in the development of SLE. B-cell depletion with Chimeric Antigen Receptor (CAR) T cell therapy is an exciting new therapeutic strategy to induce disease remission. CD19-targeting CAR T cell therapy has shown remarkable clinical benefit in resolving SLE in treated patients. Nonetheless, major limitations to this therapy remain. These include:

1) CD19 CAR T cells do not eliminate long-lived plasma cells that are responsible for the production of potentially pathogenic autoantibodies and could serve as a cellular reservoir for disease recurrence.

2) Due to unnatural costimulation, CAR T cells produce excessive levels of pro-inflammatory cytokines that can cause serious toxicity in the patient.

3) Depletion of B cells after therapy impairs humoral immunity and recovery is unpredictable,

4) Current CAR T cell therapies rely on cytotoxic lymphodepletion that can have significant shot and long-term toxicity.

These limitations highlight the need for novel therapeutic strategies with limited side-effects and for preclinical models to evaluate these new approaches. We recently introduced a synthetic chimeric T cell receptor (ChTCR) that replicates the structure of natural TCRs, confers superior antigen sensitivity compared to CARs and previous hybrid TCRs, is more effective in tumor models than CARs without producing excessive cytokines, and is readily adapted for sensitive bispecific targeting of CD19+ B cells and BCMA+ plasma cells. Our proposal will optimize a Bi-ChTCR targeting CD19 and BCMA antigens to simultaneously eliminate CD19+ B cells and BCMA+ plasma cells and incorporate a safety switch to enable physician-controlled elimination and recovery of humoral immunity. Bi-ChTCR T cell therapy will be compared to mono-specific CD19- and BCMA-specific CAR therapies using a new humanized mouse model that recapitulates B cell and T cell diversity, allows for long term follow up, and in which SLE can be induced with pristane. Our proposal will use cutting edge synthetic biology and a novel mouse model to advance our understanding of SLE pathophysiology and determine the potential of T cells engineered with a novel bispecific Chimeric TCR to safely resolve SLE. These studies will provide insight into the respective roles of B cells and plasma cells in SLE pathogenesis and advance new concepts in cellular therapy for SLE and potentially other autoimmune diseases. The specific aims are:

Aim 1: To develop a sensitive bispecific CD19/BCMA chimeric TCR (Bi-ChTCR) equipped with EGFRopt.

Aim 2: To compare the safety and efficacy of mono- and bi-specific ChTCR and CAR T cells in humanized mice with SLE and the tempo of immune reconstitution after removal of T cells with Cetuximab.