Background/Purpose: Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc) are immune mediated inflammatory diseases (IMID) where a complex interplay of tissue and immune cell activation drives a chronic loop of inflammation resulting in significant tissue damage. B cell depletion approaches highlight the contribution of B cells in IMIDs, but they are limited to targeting a single immune cell type and carry safety and tolerability risks in certain patient populations. Regulatory T cells (Tregs) are key mediators of immune and tissue homeostasis with an essential role in restraining autoimmunity. Tregs employ a wide array of mechanisms to mediate this effect and therefore can exert control over multiple immune pathways across a broad range of tissues and cell types. In IMIDs driven by complex immune responses and aberrant tissue processes such as RA and SSc, a Treg cell therapy has the unique potential to modulate multiple disease mechanisms with a single drug. In this study we describe the pre-clinical data supporting the development of QEL-005, a novel CD19 CAR-Treg product containing a FOXP3 phenotype lock. Upon infusion these CAR-Treg cells will be activated by B cells in lymph nodes and tissue resulting in a dampening of autoreactive B cell responses including autoantibody production, antigen presentation and B cell cytokine production. Moreover, through bystander suppression, activation of these CAR-Tregs will elicit modulation of other immune cells in the inflamed niche, such as autoreactive T cells and disease-associated monocytes and macrophages. This broader mechanism of action modulating multiple cell compartments differentiates CAR-Tregs from CAR-T and other conventional B-cell depletion assets.

Methods: We generated a construct containing a CAR with an FMC63 aCD19 ScFv binder and a FOXP3 phenotype lock. CD45RA+ Tregs were transduced and expanded for 14 days before cryopreservation. Thawed cells were characterised by flow cytometry to ensure CAR function and Treg stability. The mechanism of action was investigated using co-culture assays with primary human cells.

Results: QEL-005 CD19 CAR Tregs maintain a Treg phenotype, as determined by (i) a panel of Treg markers (ii) maintenance of a demethylated TSDR region, (iii) low levels of cytokine production and (iv) suppression of T cell responses. QEL-005 CAR-Tregs can be activated by CD19, driving antigen-specific proliferation and suppression but with no evidence of cytotoxicity. Culture of QEL-005 Tregs with primary B cells showed a reduction in antigen presentation potential through the depletion of CD80/86 co-stimulatory molecules, a reduction in antibody production and a reduction in B cell cytokine production. In addition, we show that co-culture of CD19 CAR Tregs with T cells and monocytes/macrophages leads to a reduction in their pro-inflammatory potential, demonstrating bystander suppression.

Conclusion: In diseases such as RA and SSc with complex interactions of immune effector and tissue cell types, QEL-005 CD19 CAR-Tregs have the potential to durably restore homeostasis in chronically inflamed tissues with limited risk of drug associated toxicity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/qel-005-cd19-car-regulatory-t-cell-therapy-a-novel-approach-for-the-treatment-of-complex-immune-mediated-inflammatory-diseases-including-rheumatoid-arthritis-and-systemic-sclerosis/