作者: Maus, Marcela V. ; Hill, Joshua A ; Frigault, Matthew J ; Liu, Katherine J ; Zhou, Baijun ; Camargo, Carlos A. ; Reynolds, Kerry ; Camargo, Carlos A ; Hong, Joseph S. ; Walter, Jolan E ; Frigault, Matthew J. ; Walter, Jolan E. ; Hong, Joseph S ; Barmettler, Sara ; Maus, Marcela V ; Hill, Joshua A. ; Ong, Mei-Sing ; Liu, Katherine J. ; Pak, Andrew ; Sutherland, Natalia M. ; Zhang, Lingxiao ; Sutherland, Natalia M

BACKGROUND:

CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19⁺ receptors on B cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse.

OBJECTIVES:

We sought to evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality.

METHODS:

We performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (IgG ≤600 mg/dL), infections prior to and after CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality.

RESULTS:

Patients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy levels (587 to 362 mg/dL; P < .0001). Thirty-seven percent of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia prior to CAR-T therapy was associated with worsening hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia post CAR-T therapy was associated with an increased risk of serious infection following CAR-T therapy (incidence rate ratio: 2.7; 95% CI: 1.5-5.2; P = .002). Risk factors for mortality included mild hypogammaglobulinemia (400 mg/dL < IgG ≤ 600 mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality.

CONCLUSIONS:

We identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia before CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia after CAR-T therapy, which was associated with an increased risk of serious infection and mortality post CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.

2025-01-01·AUTOIMMUNITY REVIEWS

Treatment of two pediatric patients with refractory systemic lupus erythematosus using CD19-targeted CAR T-cells

Letter

作者: Lu, Meiping ; Zheng, Chen ; Liu, Fei ; Zhang, Yingzi ; Hu, Bin ; Wang, Jingjing ; Ma, Daqing ; Qian, Cheng ; Shen, Junjie ; Yang, Zhi ; He, Xue ; Mao, Jianhua ; Li, Qiuyu

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising strategy for treating autoimmune diseases, particularly in systemic lupus erythematosus (SLE). However, CAR T-cell therapy for pediatric patients with SLE remains unexplored. Herein, we present a compelling investigation of two pediatric patients with refractory SLE who underwent infusion of CD19-targeted CAR T-cells. Patients 1 and 2 tolerated the CAR T-cell therapy well, which demonstrated remarkable efficacy after five and four months, respectively.

2024-04-01·Cytotherapy

A novel multicolor fluorescent spot assay for the functional assessment of chimeric antigen receptor (CAR) T-cell products

Article

作者: Baker, Jillian M ; Oluwafemi, Ayooluwakiitan ; Dahiya, Saurabh ; Avila, Stephanie V ; Atanackovic, Djordje ; Rapoport, Aaron P ; Hardy, Nancy M ; Fan, Xiaoxuan ; Gebru, Etse ; Omili, Destiny ; Hankey, Kim ; Yared, Jean A ; Dishanthan, Nishanthini ; Luetkens, Tim ; Kocoglu, Mehmet ; Dietze, Kenneth A ; Iraguha, Thierry

BACKGROUND AIMS:

Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies have revolutionized the treatment of B-cell lymphomas. Unfortunately, relapses after CD19-targeted CAR-T are relatively common and, therefore, there is a critical need for assays able to assess the function and potency of CAR-T products pre-infusion, which will hopefully help to optimize CAR-T therapies. We developed a novel multicolor fluorescent spot assay (MFSA) for the functional assessment of CAR-T products on a single-cell level, combining the numerical assessment of CAR-T products with their functional characterization.

METHODS:

We first used a standard single-cell interferon (IFN)-γ enzyme-linked immune absorbent spot assay to measure CD19-targeted CAR-T responses to CD19-coated beads. We then developed, optimized and validated an MFSA that simultaneously measures the secretion of combinations of different cytokines on a single CAR-T level.

RESULTS:

We identified IFN-γ/tumor necrosis factor-α/granzyme B as the most relevant cytokine combination, and we used our novel MFSA to functionally and numerically characterize two clinical-grade CAR-T products.

CONCLUSIONS:

In conclusion, we have developed a novel assay for the quantitative and functional potency assessment of CAR-T products. Our optimized MFSA is cost-effective, easy to perform, reliable, can be performed overnight, allowing for a fast delivery of the product to the patient, and requires relatively minimal maintenance and training. The clinical value of our novel assay will be assessed in studies correlating the pre-infusion assessment of CAR-T products with the patients' outcome in a prospective fashion.

项与 CD19靶向CAR-T--FlowTune (星尘生物) 相关的新闻（医药）

2024-07-22

·药精通Bio

CAR-T细胞疗法治疗系统性红斑狼疮，疗效可期！

TIS2024第四届自免疾病细胞疗法与干细胞疗法论坛重磅来袭，详询：王晨 180 1628 8769 系统性红斑狼疮（SLE）是一种多系统受累、高度异质性的自身免疫病，发病机制复杂，且好发于育龄期女性。SLE的临床表现具有高度异质性，系统受累不同，病程和疾病严重程度不一，可表现为发热、皮肤黏膜和肌肉骨骼损坏或肾脏、肺、心脏等多个身体器官受累。在治疗方面，SLE的治疗药物有激素、抗疟药、免疫抑制剂和生物制剂等[1]。然而，很多患者不仅需要长期用药，且用药后仍不能控制病情，无法实现长期缓解。近些年，有研究发现，靶向CD19的CAR-T细胞疗法治疗治疗SLE效果良好，能实现长期缓解。 CAR-T细胞疗法是一种基于T细胞的基因工程疗法，可以通过基因工程使T细胞识别B细胞表面的CD19和其他抗原，进而针对B细胞进行定向攻击，对于B细胞恶性肿瘤的治疗非常有效。截至目前，已有多款CAR-T细胞疗法获批上市，主要用于血液类肿瘤的治疗。早在2021年，《新英格兰医学杂志》（NEJM）上发表的一篇临床研究显示，在一名20岁的、应用多种药物治疗仍无法控制症状的严重SLE女性患者中，首次应用CAR-T细胞疗法治疗后，使得这名难治性患者的病情迅速缓解[2]。图：CAR-T细胞疗法治疗耐药性SLE患者随后，2022年发表在《nature medicine》上的一篇研究表明，通过CAR-T细胞疗法治疗5名SLE患者，3个月后所有患者都实现了SLE的缓解，且在长达17个月的随访中没有复发，均实现了无药物缓解[3]。图：CAR-T细胞在体内的扩增和B细胞的耗竭而在2023年举行的美国血液学学会年会上，一项关于CAR-T细胞疗法治疗15名自身免疫性疾病患者的研究结果显示，15名自身免疫疾病患者（包括8名系统性红斑狼疮患者、4名系统性硬化症患者和3名特发性炎性肌病患者）接受CAR-T细胞疗法后“重获新生”，患者的疾病症状得到显著改善，并实现持久的无药物缓解。所有8名SLE患者在3个月后均达到完全缓解，并自此持续维持SLE疾病活动指数（SLEDAI）为0[4]。值得一提的是，2023年，CAR-T免疫细胞疗法瑞基奥仑赛注射液（2021年在国内上市）获得临床试验默示许可，用于治疗中重度难治性SLE，以期为广大SLE患者带来新的治疗方案[5]。图：国家药品监督管理局药品评审中心除了临床研究取得的良好成果，国内多家医院也在CAR-T治疗SLE方面获得好成绩。如[6]： • 2024年3月，浙江大学医学院附属儿童医院等团队使用CAR-T疗法治疗12岁难治性SLE患者疗效良好，患儿已经顺利出院，有望得到彻底治愈。 • 2024年4月，武汉协和医院风湿免疫科利用通用型CD19 CAR-γδT治疗严重性SLE患者，三次回输CAR-γδT细胞28天后，患者的SLE疾病活动指数评分降为5分，较回输前明显下降，且期间没有服用任何其他SLE药物。 • 2024年4月，浙江大学医学院附属第一医院风湿免疫科使用靶向CD19通用型CAR-T细胞治疗难治性SLE患者，经治后患者的SLEDAI评分从治疗前的18分降为0分，并逐渐停用了所有激素和免疫抑制剂。 • 2024年5月8日，华中首个CAR-T细胞免疫治疗门诊在武汉协和医院正式启用，整合多学科专家资源，为多发性骨髓瘤、淋巴瘤、白血病、SLE等患者提供个体化、精准化的诊疗方案。随着医疗技术水平的不断提升，CAR-T细胞疗法在研究治疗严重SLE患者中取得了良好的疗效。期待这一疗法能不断创造奇迹，为SLE患者带来“治愈”的希望，实现长期无药物缓解。由中国继续医学教育网编辑整理参考资料： [1] 沈南, 赵毅, 段利华, 等. 系统性红斑狼疮诊疗规范 [J] . 中华内科杂志, 2023, 62(7) : 775-784. DOI: 10.3760/cma.j.cn112138-20221027-00793. [2] Dimitrios Mougiakakos, M.D. Gerhard Krönke, et al. M.D.CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med 2021;385:567-569 [3] Mackensen, Müller, Mougiakakos. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5 [4] Fabian Mueller MD, Jule Taubmann MD. et al. CD19-Targeted CAR-T Cells in Refractory Systemic Autoimmune Diseases: A Monocentric Experience from the First Fifteen Patients. Volume 142, Supplement 1, 2 November 2023, Page 220 [5] 国家药品监督管理局药品评审中心 [6] 武汉协和医院、武汉协和医院风湿免疫科、浙大儿院、浙一血液公众号 END 免责声明：来源干细胞之父平台往期发布内容，本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。 TIS2024第四届免疫细胞疗法与干细胞疗法论坛重磅来袭，详询：王晨 180 1628 8769

细胞疗法免疫疗法基因疗法临床研究

100 项与 CD19靶向CAR-T--FlowTune (星尘生物) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
急性淋巴细胞白血病	临床前	中国	星尘生物科技（上海）有限公司初创企业	2024-06-21
自身免疫性疾病	临床前	中国	星尘生物科技（上海）有限公司初创企业	2024-06-21
原发性中枢神经系统淋巴瘤	临床前	中国	星尘生物科技（上海）有限公司初创企业	2024-06-21