Auth Janina, Müller Fabian, Völkl Simon, Bayerl Nadine, Distler Jörg H W, Tur Carlo, Raimondo Maria G, Chenguiti Fakhouri Sara, Atzinger Armin, Coppers Birte, Eckstein Markus, Liphardt Anna-Maria, Bäuerle Tobias, Tascilar Koray, Aigner Michael, Kretschmann Sascha, Wirsching Andreas, Taubmann Jule, Hagen Melanie, Györfi Andrea-Hermina, Kharboutli Soraya, Krickau Tobias, Dees Clara, Spörl Silvia, Rothe Tobias, Harrer Thomas, Bozec Aline, Grieshaber-Bouyer Ricardo, Fuchs Florian, Kuwert Torsten, Berking Carola, Horch Raymund E, Uder Michael, Mackensen Andreas, Schett Georg, Bergmann Christina
Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Lancet Rheumatol. 2025 Feb;7(2):e83-e93. doi: 10.1016/S2665-9913(24)00282-0. Epub 2024 Nov 11.
CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown remarkable outcomes in patients with systemic lupus erythematosus. The effects of CD19-targeting CAR T cells on organ manifestations in patients with systemic sclerosis have yet to be characterised. B cells have a central role in the pathogenesis of systemic sclerosis. We present a detailed analysis of the effects of CD19-targeting CAR T-cell therapy in patients with systemic sclerosis.
Six patients with severe diffuse systemic sclerosis with an insufficient response to at least two treatments were consecutively recruited at the Department of Internal Medicine 3, University Hospital Erlangen (Erlangen, Germany) to receive CD19-targeting CAR T-cell treatment (1 × 10 CAR T cells per kg bodyweight). Events were predefined by progression of interstitial lung disease, onset of congestive heart failure, onset of renal failure, onset of arterial hypertension, or initiation of new immunosuppressive or antifibrotic therapy. Event-free time or treatment intensification after study entry was the primary outcome. Key secondary outcomes included changes in the modified Rodnan Skin Score (mRSS), imaging (a component of the assessment of lung fibrosis), laboratory assessments, patient-reported outcomes, and a modified version of the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS), assessed at baseline, 3 months, 6 months, 9 months, and 12 months.
Between April 20, 2022, and Nov 8, 2023, six patients with severe diffuse systemic sclerosis (median age 42 years [IQR 36-53]; four men and two women; all White European) were recruited and received CD19-targeted CAR T-cell therapy. The median follow-up time was 487 days (IQR 342-585). No events occurred within the observational period. Probability of improvement in the ACR-CRISS score increased to a median of 100% (IQR 100-100) at 6 months. Median mRSS decreased by 31% (IQR 29-38), corresponding to a median of 8 points (IQR 7-13) within 100 days. The extent of disease on CT scan decreased by a median of 4% (IQR 3-4) due to reduction of ground-glass opacities while the reticular pattern remained stable. Forced vital capacity improved by a median of 195 mL (IQR 18-275) at the latest observational timepoint.
We provide the first evidence that CD19-targeting CAR T-cell therapy might intercept with the progression of fibrotic organ manifestations in patients with systemic sclerosis.
Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, ELAN-Foundation Erlangen, IZKF Erlangen, and Bundesministerium für Bildung und Forschung.
靶向CD19的嵌合抗原受体（CAR）T细胞疗法在系统性红斑狼疮患者中已显示出显著疗效。靶向CD19的CAR T细胞对系统性硬化症患者器官表现的影响尚未明确。B细胞在系统性硬化症的发病机制中起核心作用。我们对靶向CD19的CAR T细胞疗法在系统性硬化症患者中的疗效进行了详细分析。
在德国埃尔朗根大学医院内科3部连续招募了6例对至少两种治疗反应不佳的重度弥漫性系统性硬化症患者，接受靶向CD19的CAR T细胞治疗（每千克体重1×10个CAR T细胞）。事件预先定义为间质性肺疾病进展、充血性心力衰竭发作、肾衰竭发作、动脉高血压发作或开始新的免疫抑制或抗纤维化治疗。研究入组后的无事件时间或治疗强化是主要结局。关键次要结局包括改良Rodnan皮肤评分（mRSS）、影像学（肺纤维化评估的一个组成部分）、实验室评估、患者报告结局以及系统性硬化症美国风湿病学会综合反应指数改良版（ACR-CRISS）在基线、3个月、6个月、9个月和12个月时的变化。
在2022年4月20日至2023年11月8日期间，招募了6例重度弥漫性系统性硬化症患者（中位年龄42岁[四分位间距36 - 53岁]；4名男性和两名女性；均为白种欧洲人）并接受了靶向CD19的CAR T细胞治疗。中位随访时间为487天（四分位间距342 - 585天）。观察期内未发生任何事件。ACR-CRISS评分改善的概率在6个月时增至中位数100%（四分位间距100 - 100）。mRSS中位数下降了31%（四分位间距29 - 38），相当于100天内中位数下降8分（四分位间距7 - 13）。由于磨玻璃影减少，CT扫描显示的疾病范围中位数下降了4%（四分位间距3 - 4），而网状模式保持稳定。在最近观察时间点，用力肺活量中位数改善了195 mL（四分位间距18 - 275）。
我们提供了首个证据，表明靶向CD19的CAR T细胞疗法可能会阻断系统性硬化症患者纤维化器官表现的进展。
德国研究基金会、德国癌症援助组织、埃尔朗根ELAN基金会、埃尔朗根跨学科临床研究中心以及德国联邦教育与研究部。
