This is a phase I dose-finding trial of an autologous CD22 targeting chimeric antigen receptor (CAR)-T cell product, called CLIC-2201, for participants with relapsed/refractory B cell malignancies. In the proposed trial, eligible enrolled participants will undergo leukapheresis for autologous T cell collection to enable CLIC-2201 manufacturing, followed by lymphodepletion with cyclophosphamide and fludarabine, then intravenous infusion of the autologous CLIC-2201 product. The trial will use the 3+3 design to escalate or de-escalate the dose level of CLIC-2201 administered. Participants will be monitored for safety and tolerability up to day 365 following CLIC-2201 infusion.
The primary objective is to evaluate the safety and tolerability of CLIC-2201 and estimate the maximum tolerated dose (MTD) of CLIC-2201 in B-cell malignancies.
The secondary objectives are to evaluate the (i) feasibility; (ii) anti-tumour activity of CLIC-2201; (iii) and characterize the pharmacokinetic (PK) profile of CLIC-2201.
Exploratory objectives will include: i) characterizing the cellular and humoral immune responses against CLIC-2201 up to 1 year following infusion of CLIC-2201; (ii) characterizing the phenotype and gene expression profile of CLIC-2201 cells; (iii) evaluating immune and tumour cells at baseline and relapse for biomarkers of response or toxicity; (iv) evaluating serum cytokines, circulating tumour DNA (ctDNA) and B cell aplasia as biomarkers of clinical outcomes; and (v) assessing the quality of life.

开始日期2024-11-01

申办/合作机构

British Columbia Cancer Agency

NCT06641024 / Not yet recruiting临床1期

Phase I Clinical Study of CD19-targeting Chimeric Antigen Receptor T Lymphocyte (MC-1-50) for the Treatment of Relapsed/Refractory CD19-positive B-cell Acute Lymphoblastic Leukemia (B-ALL)

This is a single-arm, open-label, dose-escalation phase I clinical study to explore the safety, tolerability, and cytokinetic characteristics of MC-1-50 cell formulation, and to preliminarily observe the efficacy of MC-1-50 cell formulation in subjects with relapsed/refractory CD19-positive B Cell Acute Lymphoblastic Leukemia.

开始日期2024-11-01

申办/合作机构

重庆精准生物技术有限公司

[+1]

NCT06447987 / Recruiting临床1期IIT

Phase Ib Study to Evaluate Humanized CD19-Specific CAR T Cells Following Lymphodepleting Chemotherapy in Adult Patients With Relapsed/Refractory CD19+ B-Cell Acute Lymphoblastic Leukemia

This phase Ib trial tests the safety, side effects, and effectiveness of humanized (hu)CD19-chimeric antigen receptor (CAR) T cell therapy in treating patients with CD19 positive B-cell acute lymphoblastic leukemia (ALL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR T-cell therapy is a treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein, such as CD19, on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a chimeric antigen receptor (CAR). Large numbers of the huCD19 positive CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. huCD19-CAR T cell therapy may be safe, tolerable and effective in treating patients with relapsed or refractory CD19 positive ALL.

开始日期2024-10-06

申办/合作机构

Hope Medical Center

[+1]

100 项与 CD19阳性B细胞急性淋巴细胞白血病相关的临床结果

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100 项与 CD19阳性B细胞急性淋巴细胞白血病相关的转化医学

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0 项与 CD19阳性B细胞急性淋巴细胞白血病相关的专利（医药）

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项与 CD19阳性B细胞急性淋巴细胞白血病相关的文献（医药）

2024-12-31·Cancer Biology & Therapy

Dynamic evolution of bone marrow adipocyte in B cell acute lymphoblastic leukemia: insights from diagnosis to post-chemotherapy

Article

作者: Chen, Kai ; Jia, Xi ; Liao, Naying ; Shi, Pengcheng ; Guo, Xutao ; Yao, Yunqian

Adipocyte is a unique and versatile component of bone marrow microenvironment (BMM). However, the dynamic evolution of Bone Marrow (BM) adipocytes from the diagnosis of B cell Acute Lymphoblastic Leukemia (B-ALL) to the post-treatment state, and how they affect the progression of leukemia, remains inadequately explicated. Primary patient-derived xenograft models (PDXs) and stromal cell co-culture system are employed in this study. We show that the dynamic evolution of BM adipocytes from initial diagnosis of B-ALL to the post-chemotherapy phase, transitioning from cellular depletion in the initial leukemia niche to a fully restored state upon remission. Increased BM adipocytes retards engraftment of B-ALL cells in PDX models and inhibits cells growth of B-ALL in vitro. Mechanistically, the proliferation arrest of B-ALL cells in the context of adipocytes-enrichment niche, might attribute to the presence of adiponectin secreted by adipocytes themselves and the absence of cytokines secreted by mesenchymal stem cell (MSCs). In summary, our findings offer a novel perspective for further in-depth understanding of the dynamic balance between BMM and B-ALL.

2024-10-01·Nature Genetics

Defining heritability, plasticity, and transition dynamics of cellular phenotypes in somatic evolution

Article

作者: D'Avino, Andrew R ; Schiffman, Joshua S. ; D’Avino, Andrew R. ; Rajagopalan, Srinivas ; Landau, Dan A. ; Suvà, Mario L. ; Schiffman, Joshua S ; Potenski, Catherine ; Suvà, Mario L ; Hara, Toshiro ; Fan, Yilin ; Prieto, Tamara ; Gawad, Charles ; Pang, Yakun ; Landau, Dan A

Single-cell sequencing has characterized cell state heterogeneity across diverse healthy and malignant tissues. However, the plasticity or heritability of these cell states remains largely unknown. To address this, we introduce PATH (phylogenetic analysis of trait heritability), a framework to quantify cell state heritability versus plasticity and infer cell state transition and proliferation dynamics from single-cell lineage tracing data. Applying PATH to a mouse model of pancreatic cancer, we observed heritability at the ends of the epithelial-to-mesenchymal transition spectrum, with higher plasticity at more intermediate states. In primary glioblastoma, we identified bidirectional transitions between stem- and mesenchymal-like cells, which use the astrocyte-like state as an intermediary. Finally, we reconstructed a phylogeny from single-cell whole-genome sequencing in B cell acute lymphoblastic leukemia and delineated the heritability of B cell differentiation states linked with genetic drivers. Altogether, PATH replaces qualitative conceptions of plasticity with quantitative measures, offering a framework to study somatic evolution.

2024-10-01·Journal of Infection and Public Health

Treatment of persistent coronavirus disease 2019 (COVID-19) in a B cell acute lymphoblastic leukemia patient with using nirmatrelvir/ritonavir extended course: A case report

Article

作者: Ahamed, Mohamed Firoze ; Almarhabi, Hassan ; El-Hemaidi, Ihab ; Damfu, Nader ; Alalawi, Mai ; Alharbi, Aisha

Patients with hematological malignancies are at increased risk of persistent coronavirus disease 2019 (COVID-19) infection, a unique clinical condition, for which the optimal treatment is unknown. Here we report a case of persistent COVID-19 in acute lymphoblastic leukemia (ALL) patient who successfully responded to extended course nirmatrelvir/ritonavir.

项与 CD19阳性B细胞急性淋巴细胞白血病相关的新闻（医药）

2024-07-20

·CPHI制药在线

浅谈R/R B-ALL进展：CAR-T疗法或成主流

关注并星标CPHI制药在线急性淋巴细胞白血病（ALL）是一种早期分化受阻的淋巴细胞恶性增殖性疾病，可侵犯骨髓、外周血及髓外组织，以B淋巴细胞白血病（B-ALL）为主。B-ALL在儿童急性白血病中的发病率约为80%，在成人急性白血病的发病率为20%。随着医学技术的进步，B-ALL的治疗已取得可喜进展，尤其是儿童B-ALL。不过一线治疗后，近50%的成人B-ALL患者和高达20%的儿童B-ALL患者最终会复发或原发耐药。B-ALL患者一旦出现复发或难治（R/R），患者长期生存结局堪忧，中位生存期仅3.3个月。近年批准的R/R B-ALL新疗法据不完全统计，近年来全球监管机构已批准多款R/R B-ALL药物，详见下表。这几款药物作用靶点比较集中，主要为CD19。药物类型上，这几款药物以CAR-T疗法为主，不过涉及的药物类型均是医药领域的热门赛道。具体适应症上，这几款药物几乎均被批准用于治疗成人R/R B-ALL。在研R/R B-ALL疗法进展目前，全球还有多款在研R/R B-ALL新疗法，其中obecabtagene autoleucel (obe-cel)、pCAR-19B(普基仑赛)进展较快，目前已申请上市。其中Obe-cel是Autolus Therapeutics开发的一种CD19靶向自体CAR-T疗法，其设计的嵌合抗原受体在与CD19结合后具有较快的解离速度，从而能够尽量减少T细胞的过度激活，在降低毒副作用的同时，不易发生T细胞耗竭，提高CAR-T疗法的持久性。 2024 ASCO上公布的Obe-cel治疗R/R B-ALL的开放标签、单臂1b/2期临床试验FELIX数据显示：截至2023年9月13日，共127名患者接受了Obe-cel输注，中位随访16.6个月，78%的患者达到完全缓解或不完全计数恢复的完全缓解。缓解患者中，17%（17/99）在缓解期间进行了巩固性造血干细胞移植（SCT），所有17名患者均处于可测量残留病灶（MRD）阴性缓解状态，其中59%（10/17）在SCT前显示出CAR-T细胞持续性。与持续CAR-T细胞患者相比，失去CAR-T细胞持续性复发或死亡的风险增加2.9倍。与未恢复B细胞的患者相比，经历B细胞恢复的患者复发或死亡的风险增加1.7倍。12个月时，无论是否考虑巩固性SCT或新疗法的审查，EFS（无时间生存期）率分别为50%和43%；无论是否考虑SCT的审查，OS率分别为61%和59%。目前，Obe-cel治疗R/R B-ALL的BLA正在美国接受审查，预计今年11月将收到FDA回复。 pCAR-19B是精准生物自主研发的一款CD19靶向CAR-T疗法，其采用更为安全的基因转导载体系统，从而具有更好的有效性和安全性。2023年11月，pCAR-19B被CDE纳入突破性治疗品种，用于治疗3~21岁CD19阳性R/R B-ALL。已公布的pCAR-19B针对儿童和青少年B-ALL的注册临床试验结果显示：入组的9例患者均获得完全缓解（CR），总体缓解率达100%，且首次达到CR的患者MRD也均为阴性；无剂量限制性毒性（DLT）和治疗相关死亡事件发生，总体安全性和耐受性良好。 2024年6月，pCAR-19B被CDE拟纳入优先审评，用于治疗3～21岁CD19阳性R/R B-ALL。此外，AZD0486、CN201、UCART22、GC007g、GC012F等也被开发用于治疗R/R B-ALL。其中AZD0486是TeneoTwo研发的一款新型全人源CD19 x CD3 IgG4双特异性抗体，阿斯利康通过收购TeneoTwo将其纳入囊中。AZD0486含有独特的低亲和力抗CD3片段，旨在减少细胞因子释放，同时保留T细胞介导的对恶性B细胞的有效细胞毒性。沉默的Fc段可防止非特异性结合及抗体依赖性细胞毒性，并具有适合间歇性给药的长半衰期。临床前研究显示，AZD0486通过与CD19（B细胞上表达的抗原）和T细胞上的CD3受体结合，激活T细胞并将其募集到表达CD19的肿瘤中，引发免疫反应。2024年3月，AZD0486在国内获批临床，用于治疗R/R B-ALL。 CN201是同润生物开发的一款CD19/CD3靶向双抗，其在结构上进行了一定的优化，增加了Fc段，并改良了CD3端的结构，以调节CD3端的亲和力减低细胞因子释放综合征。 2024 ASCO上公布的CN201治疗成人R/R B-ALL的1期临床试验数据显示：截至2024年1月31日，共42名成人患者接受了从600mg至40mg的全剂量CN201治疗。在37名可评估疗效的患者中，尚未达到最大耐受剂量。6名患者（14.3%）发生了3级或更高级别的感染。疗效上，37名患者中有11名（30%）实现了CR，1名（2.7%）患者实现了不完全血液学恢复的完全缓解（CRi），75%的有反应者达到了MRD阴性。随着剂量的降低，CR率显著增加，10mg目标剂量时CR率达到50%，其中两名在CN201治疗后的前两周内发生。这些有反应的患者中，100%为MRD阴性。高剂量水平患者的CR率仍在调查中。 UCART22是基于基因编辑技术TALEN和Cellectis开创性的电穿孔系统PulseAgile开发的同种异体基因编辑CAR-T疗法，靶向CD22，被开发用于治疗成人R/R B-ALL。据公司官方称，UCART22是目前开发用于治疗R/R B-ALL的疗法中最先进的同种异体CAR-T疗法。 GC007g和GC012F均由亘喜生物研发，其中GC007g是一款靶向CD19的供者来源异基因CAR-T细胞疗法，GC012F是一款CD19/BCMA双靶点自体FasTCAR-T疗法，其使用开创性的FasTCAR次日生产技术，相对于传统技术生产的CAR-T，具有更年轻的CAR-T细胞表型，并在临床前动物模型研究中，展现出强劲的肿瘤杀伤能力。总结新疗法的涌现改变了很多疾病的治疗格局，R/R B-ALL也不例外。CAR-T、双抗、ADC等热门疗法目前已闯进了R/R B-ALL治疗领域，尤其是CAR-T疗法。《中国临床肿瘤学会(CSCO)恶性血液病诊疗指南2024》已将CAR-T疗法均由II级推荐提升至I级推荐，用于Ph阳性R/R B-ALL。值得骄傲的是，我国药企在R/R B-ALL领域也有斩获，合源生物的纳基奥仑赛已率先出线，精准生物的pCAR-19B已被CDE纳入优先审评。 END 【智药研习社抗体系列直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

细胞疗法临床结果免疫疗法ASCO会议

2024-07-20

·医药观澜

总体缓解率达100%，精准生物CAR-T产品申报上市，针对白血病

▎药明康德内容团队报道今日（7月20日），中国国家药监局（NMPA）药品审评中心（CDE）官网公示，重庆精准生物的pCAR-19B细胞自体回输制剂（普基仑赛注射液）已经提交新药上市申请，并获得受理。2023年11月，该产品被CDE纳入突破性治疗品种，用于治疗3~21岁患有CD19阳性复发/难治性急性淋巴细胞白血病（ALL）的患者。截图来源：CDE官网公开资料显示，普基仑赛注射液由精准生物自主研发，是针对CD19阳性B细胞起源的恶性血液系统疾病而开发的CAR-T细胞免疫治疗产品。该产品对CAR结构进行了优化，同时采用更为安全的基因转导载体系统，从而使其具有潜在更好的有效性和安全性。普基仑赛注射液用于儿童、青少年B细胞急性淋巴细胞白血病（B-ALL）适应症于2019年在中国获批开展注册临床研究。根据早前公布的1期注册临床数据，入组的9例患者均获得完全缓解（CR），总体缓解率达100%，且首次达到完全缓解（CR）的患者微小残留病变也均为阴性，且总体安全性和耐受性良好。图片来源：中国临床试验登记与信息公示平台官网根据中国临床试验登记与信息公示平台的公示，pCAR-19B细胞自体回输制剂正在开展两项2期临床研究，分别用于治疗3-21岁患有CD19阳性复发难治性急性淋巴细胞白血病患者，以及22-70岁患有CD19阳性复发/难治性B细胞急性淋巴细胞白血病患者。该两项研究的计划招募200名患者，每项研究100名。除了白血病，普基仑赛注射液也在开展用于治疗弥漫大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤的研究。公开信息显示，精准生物致力于开发基因和细胞药物。该公司已经建立十余条产品研发管线，涉及白血病、淋巴瘤、骨髓瘤、肾癌、结直肠癌、肺癌、乳腺癌等治疗领域。除了普基仑赛注射液，该公司还有多个CAR-T细胞在研产品处于临床研究阶段。 C-4-29细胞制剂，正在开发针对肾细胞癌（实体瘤）和多发性骨髓瘤（血液肿瘤）的临床研究。 C-13-60细胞制剂：一款靶向CEA的CAR-T产品，其用于治疗实体瘤的临床研究正在开展。该产品的腹腔局部用药方式，有望突破传统静脉输注方式的局限性，增强对实体瘤杀伤能力。 MC-1-50细胞制剂：一款靶向CD19的CAR-T细胞产品，其用于治疗复发/难治性CD19阳性B细胞非霍奇金淋巴瘤患者以及复发/难治性CD19阳性B细胞急性淋巴细胞白血病患者的两项申请已于2023年下半年获批开展临床研究。参考资料： [1]中国国家药监局药品审评中心官网. Retrieved July 20， 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c [2]精准生物研发管线. Retrieved July 20， 2023, https://www.precision-biotech.com/FIELDS%20AND%20PIPELINE.html 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

细胞疗法免疫疗法ASH会议临床2期申请上市

2024-06-17

·Pharmaceutical Technology

FDA approves Amgen’s BLINCYTO for acute lymphoblastic leukaemia

In a Phase III trial, Amgen’s BLINCYTO plus consolidation chemotherapy significantly improved overall survival versus chemotherapy alone. Credit: JHVEPhoto / Shutterstock. The US Food and Drug Administration (FDA) has approved Amgen ’s BLINCYTO (blinatumomab) for CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukaemia (B-ALL) patients in the consolidation phase. This new indication for BLINCYTO is for adults and paediatric patients aged over one month with B-ALL, irrespective of the measurable residual disease status. The approval is based on the Phase III E1910 clinical trial, led by ECOG-ACRIN Cancer Research Group, which evaluated BLINCYTO in the postinduction consolidation treatment phase of newly diagnosed patients. The study aimed to deepen remission and achieve long-term responses. Trial data showed that adding BLINCYTO to consolidation chemotherapy significantly improved overall survival (OS) compared to chemotherapy alone. See Also: Monlunabant by Inversago Pharma for Obesity: Likelihood of Approval Monlunabant by Inversago Pharma for Metabolic Syndrome: Likelihood of Approval The three-year OS rate was 84.8% for patients receiving BLINCYTO plus chemotherapy, versus 69% for those on chemotherapy alone. After four and a half years of median follow-up, the five-year OS was 82.4% in the BLINCYTO and chemotherapy arm versus 62.5% in the chemotherapy group. Amgen research and development executive vice-president and chief scientific officer Jay Bradner stated: “B-ALL is an aggressive blood cancer with enduring high unmet need. BLINCYTO has helped thousands of patients with B-ALL over the last 10 years. “The approval in the frontline consolidation phase, regardless of MRD status, allows us to reach more patients than ever with this transformative first-in-class bispecific T-cell engager (BiTE) therapy.” BLINCYTO, a (BiTE) immuno-oncology therapy targeting CD19 surface antigens on B cells, has obtained breakthrough therapy and priority review designations from the FDA. It is already approved in the US for multiple indications such as CD19-positive B-ALL in first or second complete remission with MRD ≥0.1%, and relapsed or refractory CD19-positive B-ALL in adults and paediatric patients aged above one month. In May 2024, Amgen‘s Bkemv (eculizumab-aeeb) received FDA approval for use as the first interchangeable biosimilar to Soliris (eculizumab) for the treatment of specific rare diseases.