The Study of Autologous T Cells Expressing CD19 Chimeric Antigen Receptors Treatment of Minimal Residual Disease(MRD) of B Cell Malignancies and Then Autologous Hematopoietic Stem Cell Transplantation(Auto-HSCT)

The clinical study of CART19 Cells treatment for MRD of B Cell Malignancies and then auto-HSCT

开始日期2018-06-01

申办/合作机构

深圳市第二人民医院（深圳市转化医学研究院）

NCT03146533 / Unknown status临床1/2期IIT

Phase I/II Study of CD19 CART Cells for Patients With Relapse and Refractory CD19+ B-cell Lymphoma.

This is a clinical study to observe the maximum tolerated dose (MTD) and the safety and feasibility of chimeric antigen receptor 19 (CD19 CART) cells in relapsed and refractory patients with CD19+ B cell lymphoma.

开始日期2017-05-01

申办/合作机构

深圳市第二人民医院（深圳市转化医学研究院）

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100 项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的临床结果

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100 项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的转化医学

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100 项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的专利（医药）

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项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的文献（医药）

2022-03-08·JNCI-Journal of the National Cancer Institute1区 · 医学

Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

1区 · 医学

Article

作者: Ferrer, Gerardo ; del Bufalo, Francesca ; Juan, Manel ; Esteller, Manel ; Fernandez, Agustin F ; Quintarelli, Concetta ; Itzhaki, Orit ; Meir, Amilia ; Jacoby, Elad ; Locatelli, Franco ; Davalos, Veronica ; Soler, Marta ; Sinibaldi, Matilde ; Urbano-Ispizua, Álvaro ; Urdinguio, Rocio G ; Fraga, Mario F ; González-Navarro, Europa Azucena ; Besser, Michal J ; Delgado, Julio ; Bueno-Costa, Alberto ; Garcia-Prieto, Carlos A ; Bar, Diana ; Ortiz-Maldonado, Valentín ; Castro de Moura, Manuel ; Villanueva, Lorea ; Avigdor, Abraham

Abstract:

Background:

Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course.

Methods:

We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided.

Results:

We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02).

Conclusions:

We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.

2020-06-01·JACC. CardioOncology2区 · 医学

Cardiovascular Effects of CAR T Cell Therapy

2区 · 医学

ArticleOA

作者: Lefebvre, Bénédicte ; Scherrer-Crosbie, Marielle ; Kang, Yu ; Smith, Amanda M ; Frey, Noelle V ; Carver, Joseph R

BACKGROUND:

Anti-CD19 chimeric antigen receptor (CAR) T cell (CART19) therapy holds great promise in the treatment of hematological malignancies. A high occurrence of cardiac dysfunction has been noted in children treated with CART19 therapy.

OBJECTIVES:

We aimed to define the occurrence of major cardiovascular events (MACE) in adult patients treated with CART19 cells and assess the relationships between clinical factors, echocardiographic parameters, laboratory values, and cardiovascular outcomes.

METHODS:

Baseline clinical, laboratory and echocardiographic parameters were collected in 145 adult patients undergoing CART19 cell therapy. MACE included cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke and de novo cardiac arrhythmia. Baseline parameters associated with MACE were identified using Cox proportional cause-specific hazards regression analysis.

RESULTS:

Thirty-one patients had MACE (41 events) at a median time of 11 days (Q1-Q3:6-151 days) after CART19 cell infusion. The median follow-up period was 456 days (Q1-Q3: 128-1214 days). Sixty-one patients died. Cytokine release syndrome (CRS) occurred 176 times in 104 patients; the median time to CRS was 6 days (Q1-Q3: 1-8 days). The Kaplan-Meier estimates for MACE and CRS at 30 days were 17% and 53% respectively. The KM estimates for survival at 1 year was 71%. Multivariable Cox proportional cause-specific hazards regression analysis determined that baseline creatinine and Grade 3 or 4 CRS were independently associated with MACE.

CONCLUSION:

Patients treated with CART19 are at an increased risk of MACE and may benefit from cardiovascular surveillance. Further large prospective studies are needed to confirm the incidence and risk factors predictive of MACE.

2019-11-01·Current opinion in hematology3区 · 医学

Mechanisms of failure of chimeric antigen receptor T-cell therapy

3区 · 医学

Review

作者: Li, Xiaoqing ; Chen, Weihong

Purpose of review:

Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate.

Recent findings:

We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19- subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors – paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid.

Summary:

Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system.

Video abstract:

Although Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com.libproxy1.nus.edu.sg/COH/A18.

项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的新闻（医药）

2024-03-01

·生物制药小编

自免CAR-T的四大技术路线

近日，随着CD19-CAR-T在自免领域最新临床数据在《NEJM》上的发布，这一条曾经不被看好赛道的前景也逐步明朗。像红斑狼疮那样难以根治的自免疾病或许将因CAR-T而不再困难。所有患者在接受治疗后的中位随访15个月内，都能够做到停止使用免疫抑制剂来进行后续治疗。甚至有患者在经过治疗2年之内，都没有再复发的迹象，可以说完全重建了B细胞，展现出了CAR-T潜在的持久性。本文将梳理目前自免领域CAR-T的概览情况和未来发展方向，赛道竞争者，及其不同的开发方式。自免CAR-T情况概览从机制上来看，目前CAR-T在人体临床中所治疗的自身免疫病主要是B细胞介导的自身免疫病。因为B细胞介导的自身免疫性疾病主要涉及B细胞的异常活化，异常活化的B细胞会产生大量的自身抗体，这些自身抗体攻击自身组织，导致组织损伤和疾病发生。常用的疗法如利妥昔单抗，糖皮质激素一方面有药物依赖的问题，另一方面还常常会出现复发，甚至还有一些患者根本对传统疗法没有反应。而CD19/BCMA等靶点的CAR-T能够直接靶向B细胞，可以通过清除现有B细胞，并诱发B细胞重建来实现治疗目的。而在CD19基础上的CD19/BCMA双靶点的逻辑有些类似癌症中的应用，双靶点可以同时靶向CD19+记忆B细胞和BCMA+浆细胞。另外又有一种CAART仅针对携带某些自身抗原受体的免疫细胞，靶标相对特殊，并没有对所有B细胞进行免疫抑制。在使用CAAR-T细胞疗法治疗自身免疫性脑炎患者中已经观察到靶细胞成功裂解。而对于T细胞介导的自身免疫性疾病，传统的CAR-T仍然因为会出现“T细胞自杀”问题而鲜有办法，目前看来可实践性不大，尚待T细胞肿瘤中临床实践的佳音。针对这一问题，另外一种可能更有希望的技术路线则在于CAR-Tregs上。Treg细胞是一种天然存在的、具有免疫抑制功能的T细胞亚群，它们对于维持机体免疫耐受和防止自身免疫反应过度至关重要。CAR-Treg疗法旨在利用工程化改造后的Treg细胞，使其能够更精确地定向到自身免疫疾病的炎症部位或参与异常反应的特定细胞类型，并通过增强局部免疫抑制作用来控制和缓解自身免疫反应。而CAR-Tregs就可以针对主要由T细胞介导的自身免疫性疾病，如1型糖尿病，GvHD（移植物抗宿主病）等。扩充了CAR在自身免疫病领域的应用格局。图1：上图展示了上文所述的CAR-T治疗自身免疫性疾病的方法。自免CAR-T竞争格局一览如下图所示，目前自免CAR-T开展的临床试验主要在中美两国，靶点主要是CD19，一部分CD19/BCMA双靶点CAR-T也在同步推进中。值得一提的是，此前阿斯利康收购亘喜生物的举动其实也补充了阿斯利康的自身免疫管线。同样布局自免CAR-T的大厂还有收购了巨诺的BMS。而在新兴Biotech公司的新注册临床中，百暨基因，邦耀生物，重庆精准，雅科生物等我国企业的出现值得期待。相比于已经在B细胞自免领域证实疗效的CD19-CAR-T，虽然近年来成立了多家相关公司，但CAR-Tregs目前大都处于临床早期和临床前阶段，适应症开发集中在GvHD上。必须开发UCAR-T的理由同样值得关注的是通用型CAR-T在自免领域上的出现，百暨基因和邦耀生物开发的两款CAR-T均为UCAR。在很多情况，CAR-T被用作针对血液肿瘤的先锋利器，而高昂的价格和成本同样也成为了困扰其普及性的重要阻碍。这一问题同样出现在自免领域。这里简单来算一笔经济账，以目前研究较多的系统性红斑狼疮（SLE）为例。在美国，不开发UCAR-T就能获得收入的逻辑相对走得通，美国平均每例SLE患者每年的疾病花费约为20924美元，而CAR-T价格在40万美元左右，只要接受CAR-T治疗后，能确保20年内不复发，对患者来说就更愿意选择CAR-T。当然确保不复发是前提，是否能确保不复发，很难得到预知。而在我国，系统性红斑狼疮每年治疗费用根据病情严重程度而分类，较为轻微的患者每年治疗花费大约在几千元内不等。病情较为严重的患者花费才相对较高，一年的治疗费用可能超过1万元。如果按照100万-120万CAR-T的价格来计算，相对性价比仍然不高，可能只有出现患者对传统治疗无反应的情况下才会采用CAR-T疗法。在这种情况下开发价格更低的UCAR-T就成为了解决问题的可能方案。总结在目前CAR-T赛道大量临床集中在肿瘤的情况下，向自免领域开发是避免内卷的方法之一，而这一领域不光是靶点，模式，修饰的细胞和靶向的细胞，都有进一步的开发可能性。参考来源：Chasov V, Zmievskaya E, Ganeeva I, Gilyazova E, Davletshin D, Khaliulin M, Kabwe E, Davidyuk YN, Valiullina A, Rizvanov A, Bulatov E. Immunotherapy Strategy for Systemic Autoimmune Diseases: Betting on CAR-T Cells and Antibodies. Antibodies (Basel). 2024 Feb 1;13(1):10. doi: 10.3390/antib13010010. PMID: 38390871; PMCID: PMC10885098.Reincke SM, von Wardenburg N, Homeyer MA, Kornau HC, Spagni G, Li LY, Kreye J, Sánchez-Sendín E, Blumenau S, Stappert D, Radbruch H, Hauser AE, Künkele A, Edes I, Schmitz D, Prüss H. Chimeric autoantibody receptor T cells deplete NMDA receptor-specific B cells. Cell. 2023 Nov 9;186(23):5084-5097.e18. doi: 10.1016/j.cell.2023.10.001. Epub 2023 Nov 1. PMID: 37918394.Nunez D, Patel D, Volkov J, Wong S, Vorndran Z, Müller F, Aigner M, Völkl S, Mackensen A, Schett G, Basu S. Cytokine and reactivity profiles in SLE patients following anti-CD19 CART therapy. Mol Ther Methods Clin Dev. 2023 Sep 1;31:101104. doi: 10.1016/j.omtm.2023.08.023. PMID: 37744005; PMCID: PMC10514439.

细胞疗法免疫疗法

100 项与 CART19 Cells(Shenzhen Second People's Hospital) 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
B细胞白血病	临床1期	中国	深圳市第二人民医院（深圳市转化医学研究院）	2018-06-01
B细胞淋巴瘤	临床1期	中国	深圳市第二人民医院（深圳市转化医学研究院）	2018-06-01
B细胞恶性肿瘤	临床1期	中国	深圳市第二人民医院（深圳市转化医学研究院）	2018-06-01