Precision Targeting of Lupus IGHV4-34+ Pathogenic B Cells with CAR T Cells

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized cancer therapy and has shown promise in people with systemic lupus erythematosus (SLE). CAR-T therapy involves engineering a patient’s T cells to recognize and attack specific cell types. To date, many CAR-T cells target CD19, a molecule found on the surface of B cells. B cells are a key player in SLE, and targeting B cells can lead to disease remission (a loss or reduction of symptoms). CD19 is found on both healthy and disease-causing B cells, and targeting CD19 eliminates B cells, even if they are not harmful. As a result, CD19 CAR-T therapy can suppress the immune system, leaving the patient at risk of harmful infections. Dr. Ruella aims to develop a safe cell therapy for people with lupus by developing CAR-T cells that target only disease-causing B cells while sparing healthy B cells.

Antibodies, produced by B cells, recognize and target foreign pathogens (like bacteria and viruses) to protect us from infections. In lupus, some of these antibodies become self-reactive, recognizing a patient’s own cells as foreign by mistake. Antibodies with a component called IGHV4-34 are typically self-reactive in SLE. High levels of these antibodies are linked to increased lupus severity. IGHV4-34 antibodies are higher than normal in lupus, but only about 5% of B cells in healthy individuals contain IGHV4-34 antibodies, pointing to their potential as a disease-specific target. Dr. Ruella and his team will optimize CAR-T cells that target IGHV4-34+ lupus-associated B cells while sparing healthy B cells. The team will then test the effectiveness of IGHV4-34-targeted CAR-T cells (CAR-T4-34) in B cells from people with SLE and in multiple mouse models of lupus to determine whether specifically depleting IGHV4-34+ B cells is an effective strategy in treating SLE.

What this study means for people with lupus

CAR-T cell therapy is shifting the paradigm of lupus treatment, and there is an unmet need to develop treatments for those with advanced SLE for whom there are few safe and effective treatments. Findings from this study could lead to a clinical trial of CAR-T4-34, possibly improving the quality of life for people with lupus.

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease characterized by a myriad of immune system aberrations that involve chiefly B cell dysregulation and activation. Remarkably, a recent study showed that chimeric antigen receptor T cells (CART) that target the pan-B-cell marker CD19 can lead to deep responses in patients with SLE. CART immunotherapy has revolutionized the field of oncology, with already 6 FDA-approved products for lymphoid malignancies. However, one major obstacle with CART19 is prolonged B-cell aplasia caused by targeting the pan-B-cell marker CD19 and the fact that CD19 is not a pathogenic driver of disease (B-cell can survive without CD19) that has led to CD19-negative escape in the clinic. Seminal studies from our group and others suggest that the IGHV4-34 antibody family plays a key role in SLE pathogenesis. IGHV434 antibodies are highly enriched in Lupus and are associated with disease severity. Furthermore, the finding that a substantial portion of IGHV4-34 antibodies recognizes nuclear antigens, as well as ss- and ds-DNA, and apoptotic cells, highlights the role of the VH4-34 antibodies in promoting SLE disease and suggests IGHV4-34 as a viable target for immunotherapy. Therefore, we hypothesize that the targeted depletion of IGHV4-34+ B cells in Lupus patients will lead to an improvement in symptoms while sparing most healthy B-cells. In Aim#1 of this project, we will optimize the CART (CART4-34) to target IGHV4-34+ B cells by altering hinge and linker length and costimulatory domain thus facilitating the interaction with IGHV4-34+ B cells. We will then test these new designs (n=30) in-vitro and in-vivo against IGHV4-34+ and -neg target cells, as well as primary B cells. We will also test the specificity and confirm that the lead construct does not impair normal B cells and hematopoiesis differently than CART19 using a humanized immune system model (NGS-BLT mice). In Aim#2, we will determine the efficacy of the novel best-in-class CART4-34 in targeting in-vitro and in-vivo Lupus models. We will first compare the efficacy and specificity of CART4-34 against healthy donor-B cells or SLE-patient-derived B cells in vitro. We will then use three innovative in-vivo SLE models to determine whether the specific depletion of IGHV4-34+ B cells with the novel CART4-34 affects disease progression. This proposal is highly innovative and relevant to the goals of the LRA Mechanisms and Targets Award and will significantly impact the field of Lupus by: i. studying a novel target and models for CAR T cell immunotherapy for SLE; ii. providing mechanistic insights as to whether depletion of IGHV4-34+ B cells will lead to remission, and; iii. ultimately improve the standard of care or quality of life of people with Lupus. This project will set the bases for a first-in-human phase I clinical trial of CART4-34 cells for IGHV4-34+ SLE.