Background/Purpose: A significant unmet need remains in the treatment of relapsed and/or refractory B cell-driven autoimmune diseases, including systemic lupus erythematosus (SLE),systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM). The presence of autoantibodies is a hallmark of such diseases and implicates dysregulated B cell function in their pathogenesis. The central role of B cells in these diseases is also supported by the presence of B cells in diseased tissues. We have recently shown that anti-CD19 chimeric antigen receptor (CAR) T cells are well tolerated and highly effective in patients with B cell-driven autoimmune diseases including SLE, IIM,and SSc (Mackensen Nat Med 2022, Muller Lancet 2023, Bergman Ann Rheum Dis 2023).KYV-101 is an autologous anti-CD19 CART cell therapy designed to deplete B cells, including autoreactive B cells. Importantly, the human anti-CD19 CAR used in KYV-101 was previously tested in B-cell lymphoma patients and demonstrated similar efficacy with an improved safety and immunogenicity profile compared to historical controls (Brudno Nat Med 2020).Since anti-CD19 CART cells target and kill a broad set of B cells in both circulation and tissues, a more complete depletion of autoreactive B cells is expected with KYV-101 leading to a greater magnitude and durability of disease control than current immunotherapies. These studies examined the CAR-mediated and CD19-dependent activity ofKYV-101 against autologous, patient-derived B cells.

Methods: Autologous CD4+ and CD8+ T cells were enriched from healthy donors (HD) or SLE, SSc, or IIMpatients.KYV-101 CAR T cells were produced following transduction with a lentiviral vector encoding a fully human second generation anti-CD19 CAR. The CAR-mediated and CD19-dependent activity of KYV-101 was monitored in vitrovia cytotoxicity, cytokine release, and proliferation studies in response to CD19+ target cell lines or autologousCD19+ B cells.

Results: Following an overnight incubation, KYV-101 generated from HDs or autoimmune patients induced greater cytotoxicity against both the human CD19+ NALM6 cell line and autologous, patient-derived primary B cells than untransduced(UNTD) control T cells. An increase in the production of cytokines such as IFNγ was also observed following co-culture. In contrast, no differences in cytotoxicity nor cytokine production were observed whenKYV-101 or UNTD control T cells were co-cultured with CD19- target cell lines. In addition, following a 96-hour incubation, KYV-101 generated from HDs or autoimmune patients proliferated when co-cultured with the NALM6 cells or autologous B cells, whereas substantially lower levels of proliferation were observed in the UNTD control T cells co-cultured with NALM6 or autologous B cells, or in KYV-101 and UNTD control T cells co-cultured with the CD19- cell lines.

Conclusion: KYV-101 generated from autoimmune disease patient lymphocytes demonstrates CAR-mediated and CD19-dependent activity against autologous B cells and thus may represent a novel therapeutic option for B cell-driven autoimmune diseases. KYV-001 is being investigated in a Phase 1 trial in adults with refractory lupus nephritis. *Soo Park and Gloria Lutzny-Geier contributed equally.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/kyv-101-a-fully-human-anti-cd19-car-t-cell-therapy-demonstrates-car-mediated-and-cd19-dependent-activity-against-autologous-b-cells-from-patients-with-autoimmune-disease/