BCMA-directed mRNA CAR-T cell therapy for myasthenia gravis: exploratory biomarker analysis of a placebo-controlled phase 2b trial.

However, adoption of cell therapies in the autoimmune space is limited by hurdles such as inpatient administration, lymphodepletion and safety concerns around cytokine release syndrome and non-specific immunosuppression.

然而，细胞疗法在自身免疫领域的应用受到限制，如住院治疗、淋巴细胞减少和细胞因子释放综合征及非特异性免疫抑制的安全性问题等障碍。

RNA-based cell therapy has potential to address these limitations.

基于RNA的细胞疗法有潜力解决这些限制。

Here we report prespecified exploratory analyses from a successful placebo-controlled, double-blind, randomized phase 2b trial in patients with generalized myasthenia gravis who received Descartes-08, an autologous, RNA-encoded anti-B cell maturation antigen (BCMA) CAR-T cell therapy.

在这里，我们报告了一项成功的安慰剂对照、双盲、随机的2b期试验的预定探索性分析结果，该试验针对的是接受Descartes-08治疗的全身型重症肌无力患者，Descartes-08是一种自体、RNA编码的抗B细胞成熟抗原（BCMA）嵌合抗原受体T细胞（CAR-T）疗法。

In 66.7% of patients (n = 10/15), transient targeting of BCMA with Descartes-08 administered in an outpatient setting without lymphodepletion resulted in durable clinical efficacy.

在66.7%的患者中（n = 10/15），在门诊环境中使用Descartes-08靶向BCMA，无需淋巴耗竭，导致了持久的临床疗效。

Comparison of Descartes-08-treated (n ≤ 19) and placebo (n ≤ 15) cohorts by flow cytometry, serum profiling, multiplexing cytokine analysis and bulk/single-cell transcriptional analysis reveals a precision retuning of self-reactivity demonstrated by increased pro-immune function, decreased activity of BCMA+ plasma cells and plasmacytoid dendritic cells and reductions in disease-associated cytokines, such as IL-6.

通过流式细胞术、血清学分析、多路复用细胞因子分析和批量/单细胞转录分析比较Descartes-08处理组（n ≤ 19）和安慰剂组（n ≤ 15），揭示了自我反应性的精确调节，表现为促免疫功能增加，BCMA+浆细胞和浆细胞样树突状细胞的活性降低，以及疾病相关细胞因子（如IL-6）的减少。

Furthermore, antibody and T cell receptor analysis revealed altered circulating repertoires of self-reactive antibodies and T cell clones among Descartes-08 participants.

此外，抗体和T细胞受体分析揭示了Descartes-08参与者中自身反应性抗体和T细胞克隆的循环库发生了改变。

These effects occurred without immune suppression, indicated by the lack of decline in vaccine-specific antibodies or hypogammaglobulinemia.

这些效应在没有免疫抑制的情况下发生，这一点通过疫苗特异性抗体没有下降或未出现低丙种球蛋白血症来表明。

Our findings unveil a new type of immune reset and support the development of BCMA-targeted RNA cell therapies as a more accessible therapy for autoimmune diseases.

我们的发现揭示了一种新的免疫重置类型，并支持开发靶向BCMA的RNA细胞疗法，作为一种更易获取的治疗自身免疫疾病的疗法。

ClinicalTrials.gov identifier: NCT04146051 .

ClinicalTrials.gov注册号：NCT04146051。