Treatment of Systemic Lupus Erythematosus using BCMA-CD19 Compound CAR.
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ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC8599262 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play central roles in B cell development and maturation. Soluble forms of their receptors can be generated by proteolytic cleavage; however, their physiological and clinical roles are unknown. This study aimed to assess the relationships between the receptor soluble B cell maturation antigen (sBCMA) and clinical variables in systemic lupus erythematosus (SLE) patients. Serum cytokine concentrations were measured by ELISA for 129 SLE patients and 34 healthy controls (HCs), and the expression of the receptor BCMA was evaluated on B and plasma cells from 40 subjects. SLE patients showed aberrant expression of the receptor BCMA on B and plasma cells. Soluble levels of the receptor sBCMA and its ligands sAPRIL and sBAFF were increased in SLE patients compared with HCs. Additionally, sBCMA (rs?=?0.6177) and sAPRIL (rs?=?0.4952) correlated strongly with disease activity. Active SLE patients who achieved low disease activity showed decreased sBCMA (53.30 vs 35.30?ng/mL; p?<?0.05) and sBAFF (4.48 vs 2.27?ng/mL; p?<?0.05) serum levels after treatment, while sAPRIL expression remained unchanged. At a cutoff value of 22.40?ng/mL, sAPRIL showed high sensitivity (96.12%) and specificity (94.12%) for discrimination between HCs and SLE patients, while sBAFF showed lower sensitivity (82.2%) but higher specificity (94.1%) at a cutoff of 1.195?ng/mL. Relatively high levels of sAPRIL and sBCMA clustered active SLE patients. The receptor sBCMA could be a potential biomarker of disease activity in SLE.
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Project description:The low rate of durable response against relapsed and/or refractory multiple myeloma (RRMM) in recent studies indicates that chimeric antigen receptor T-cell (CART) treatment is yet to be optimized. This study aims to investigate the safety and efficacy of sequential infusion of CD19-CART and B-cell maturation antigen (BCMA)-CARTs for RRMM with a similar 3 + 3 dose escalation combined with a toxicity sentinel design. We enrolled 10 patients, among whom 7 received autologous infusion and 3 received allogeneic infusion. The median follow-up time was 20 months. The most common grade 3/4 treatment-emergent toxicities were hematological toxicities. Cytokine-release syndrome (CRS) adverse reactions were grade 1/2 in 9 out of 10 subjects. No dose-limited toxicity (DLT) was observed for BCMA-CAR-positive T cells ≤5 × 107 /kg), while two patients with dose-levels of 5-6.5 × 107 /kg experienced DLTs. The overall response rate was 90% (five partial responses and four stringent complete responses). Three out of four patients with stringent complete responses to autologous CART had progression-free survival for over 2 years. The three patients with allogeneic CART experienced disease progression within 2 months. These results evidence the sequential infusion's preliminarily tolerability and efficacy in RRMM, and present a simple and safe design applicable for the establishment of multiple CART therapy.
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Project description:Systemic lupus erythematosus (SLE) T cells display a hyperactive calcineurin/NF-AT pathway. The aim of this study was to determine whether this pathway is responsible for the aberrant SLE T cell function and to test the effectiveness of the recently recognized calcineurin inhibitor dipyridamole in limiting SLE-related pathology.T cells and mononuclear cells were isolated from the peripheral blood of SLE patients and healthy individuals. Murine cells were isolated from the spleens and lymph nodes of lupus-prone MRL/lpr mice and control MRL/MpJ mice. Cells were treated in vitro with tacrolimus, dipyridamole, or control. MRL/lpr mice were injected intraperitoneally with 50 mg/kg of dipyridamole 3 times a week for 3 weeks.MRL/lpr T cells, especially CD3+CD4-CD8- cells, displayed a robust calcium influx upon activation and increased levels of NF-ATc1. MRL/lpr T cells (both CD4+ and CD3+CD4-CD8- cells) provided help to B cells to produce immunoglobulin in a calcineurin-dependent manner. Dipyridamole treatment of SLE T cells significantly inhibited CD154 expression, interferon-?, interleukin-17 (IL-17), and IL-6 production, and T cell-dependent B cell immunoglobulin secretion. Treatment of MRL/lpr mice with dipyridamole alleviated lupus nephritis and prevented the appearance of skin ulcers.NF-AT activation is a key step in the activation of SLE T cells and the production of immunoglobulin. Dipyridamole inhibits SLE T cell function and improves pathologic changes of the disease in lupus-prone mice. We propose that dipyridamole can be used in treatment regimens for patients with SLE.
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Project description:INTRODUCTION: Bullous systemic lupus erythematosus (BSLE) is an autoantibody-mediated disease with subepidermal blisters. It is a rare form of presentation of SLE that occurs in less than 5% of cases of lupus. CASE REPORT: A 27-year-old, female, FRS patient reported the appearance of painful bullous lesions in the left nasal wing and left buccal mucosa that displayed sudden and rapid growth. She sought advice from emergency dermatology staff 15 days after onset and was hospitalized with suspected bullous disease. Intravenous antibiotics and steroids were administered initially, but the patient showed no improvement during hospitalization. She displayed further extensive injuries to the trunk, axillae, and vulva as well as disruption of the bullous lesions, which remained as hyperemic scars. Incisional biopsy of a lesion in the left buccal mucosa was performed, and pathological results indicated mucositis with extensive erosion and the presence of a predominantly neutrophilic infiltrate with degeneration of basal cells and apoptotic keratinocytes. Under direct immunofluorescence, the skin showed anti-IgA, anti-IgM, and anti-IgG linear fluorescence on the continuous dermal side of the cleavage. Indirect immunofluorescence of the skin showed conjugated anti-IgA, was anti-IgM negative, and displayed pemphigus in conjunction with anti-IgG fluorescence in the nucleus of keratinocytes, consistent with a diagnosis of bullous lupus erythematosus. DISCUSSION: BSLE is an acquired autoimmune bullous disease caused by autoantibodies against type VII collagen or other components of the junctional zone, epidermis, and dermis. It must be differentiated from the secondary bubbles and vacuolar degeneration of the basement membrane that may occur in acute and subacute cutaneous lupus erythematosus.
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