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characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cellacute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia

《医学前沿（英文）》 2022年 第16卷 第1期   页码 139-149 doi: 10.1007/s11684-021-0835-8

摘要： The CD19-targeting bispecific T-cell engager blinatumomab has shown remarkable efficacy in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. However, several studies showed that blinatumomab has a short plasma half-life due to its low molecular weight, and thus its clinical use is limited. Furthermore, multiple trials have shown that approximately 30% of blinatumomab-relapsed cases are characterized by CD19 negative leukemic cells. Here, we design and characterize two novel antibodies, A-319 and A-2019. Blinatumomab and A-319 are CD3/CD19 bispecific antibodies with different molecular sizes and structures, and A-2019 is a novel CD3/CD19/CD20 trispecific antibody with an additional anti-CD20 function. Our in vitro, ex vivo, and in vivo experiments demonstrated that A-319 and A-2019 are potent antitumor agents and capable of recruiting CD3 positive T cells, enhancing T-cell function, mediating B-cell depletion, and eventually inhibiting tumor growth in Raji xenograft models. The two molecules are complementary in terms of efficacy and specificity profile. The activity of A-319 demonstrated superior to that of A-2019, whereas A-2019 has an additional capability to target CD20 in cells missing CD19, suggesting its potential function against CD19 weak or negative CD20 positive leukemic cells.

关键词： B-cell acute lymphoblastic leukemia     bispecific antibody     trispecific antibody     CD19     CD20    

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Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, Saijuan Chen

《医学前沿（英文）》 2021年 第15卷 第3期   页码 347-371 doi: 10.1007/s11684-020-0821-6

摘要： B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by genetic alterations with high heterogeneity. Precise subtypes with distinct genomic and/or gene expression patterns have been recently revealed using high-throughput sequencing technology. Most of these profiles are associated with recurrent non-overlapping rearrangements or hotspot point mutations that are analogous to the established subtypes, such as rearrangements, rearrangements, rearrangements, rearrangements, / and/or rearrangements, like gene expression, PAX5alt (diverse alterations, including rearrangements, intragenic amplifications, or mutations), and hotspot mutations PAX5 (p.Pro80Arg) with biallelic alterations, IKZF1 (p.Asn159Tyr), and ZEB2 (p.His1038Arg). These molecular subtypes could be classified by gene expression patterns with RNA-seq technology. Refined molecular classification greatly improved the treatment strategy. Multiagent therapy regimens, including target inhibitors (e.g., imatinib), immunomodulators, monoclonal antibodies, and chimeric antigen receptor T-cell (CAR-T) therapy, are transforming the clinical practice from chemotherapy drugs to personalized medicine in the field of risk-directed disease management. We provide an update on our knowledge of emerging molecular subtypes and therapeutic targets in BCP-ALL.

关键词： BCP-ALL     subtypes     translocation     aneuploidy     sequence mutations    

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Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

null

《医学前沿（英文）》 2012年 第6卷 第4期   页码 416-420 doi: 10.1007/s11684-012-0224-4

摘要：

Acute lymphoblastic leukemia includes T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL). In children, T-ALL usually has a worse prognosis than B-ALL, although childhood T-ALL prognoses have improved remarkably. The varying outcomes among T-ALL cases suggest that an unrecognized biological heterogeneity may contribute to chemo-resistance. Deep exploration of T-lymphocyte development in recent years has found a subgroup of patients with a phenotype that resembles early T-cell precursor, which confers a much poorer prognosis than any other form of T-ALL. This novel subtype of T-ALL was called early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Flow cytometry data from T-ALL patients enrolled in Shanghai Children’s Medical Center between July 2002 and October 2010 were assessed according to Dr. Campana’s protocol. Among total 89 T-ALL cases, 74 cases had enough immunophenotype data available to differentiate between ETP (CD1a-, CD8-, CD5dim, at least one marker of stem cell or myeloid lineage) and non-ETP. From these 74 subjects, 12 ETP-ALL cases (16.2%) were identified. The event-free survival (EFS) rate at 66.8 months was 11.1%±10.1% for ETP-ALL and 57.6%±5.6% for non-ETP-ALL (P=0.003). The overall survival rates were 13.3%±11.0% for ETP-ALL and 64.7%±6.3% for non-ETP-ALL (P=0.002). Our findings demonstrate that early T-cell precursor leukemia is a very high-risk subtype of acute lymphoblastic leukemia with poor prognosis.

关键词： acute lymphoblastic leukemia     early T precursor     prognosis    

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Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

《医学前沿（英文）》 2022年 第16卷 第3期   页码 442-458 doi: 10.1007/s11684-021-0877-y

摘要： T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.

关键词： T-cell acute lymphoblastic leukemia     HDAC inhibitor     chidamide     NOTCH1     MYC     ubiquitination    

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Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

《医学前沿（英文）》 2020年 第14卷 第6期   页码 689-700 doi: 10.1007/s11684-020-0759-8

摘要： The cure rate of childhood acute lymphoblastic leukemia (ALL) has exceeded 90% in some contemporary clinical trials. However, the dose intensity of conventional chemotherapy has been pushed to its limit. Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno- and cellular-therapy approaches together with precise risk stratification. Children with or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment. Patients with Philadelphia chromosome (Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib. BH3 profiling and other preclinical methods have identified several high-risk subtypes, such as hypodiplod, early T-cell precursor, immature T-cell, -rearranged, Ph-positive and -positive ALL, that may respond to BCL-2 inhibitor venetoclax. There are other fusions or mutations that may serve as putative targets, but effective targeted therapy has yet to be established. For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions, current approaches that offer hope include blinatumomab, inotuzumab and CAR-T cell therapy for B-ALL, and daratumumab and nelarabine for T-ALL. With the expanding therapeutic armamentarium, we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.

关键词： acute lymphoblastic leukemia     molecular therapeutics     targeted therapy     tyrosine kinase inhibitors     immunotherapy     CAR T-cell therapy    

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Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese

《医学前沿（英文）》 2023年 第17卷 第3期   页码 518-526 doi: 10.1007/s11684-022-0958-6

摘要： Venous thromboembolism (VTE) is a complication in children with acute lymphoblastic leukemia (ALL). The Chinese Children’s Cancer Group-ALL-2015 protocol was carried out in China, and epidemiology, clinical characteristics, and risk factors associated with VTE were analyzed. We collected data on VTE in a multi-institutional clinical study of 7640 patients with ALL diagnosed in 20 hospitals from January 2015 to December 2019. First, VTE occurred in 159 (2.08%) patients, including 90 (56.6%) during induction therapy and 108 (67.92%) in the upper extremities. T-ALL had a 1.74-fold increased risk of VTE (95% CI 1.08–2.8, P = 0.022). Septicemia, as an adverse event of ALL treatment, can significantly promote the occurrence of VTE (P < 0.001). Catheter-related thrombosis (CRT) accounted for 75.47% (n = 120); and, symptomatic VTE, 58.49% (n = 93), which was more common in patients aged 12–18 years (P = 0.023), non-CRT patients (P < 0.001), or patients with cerebral thrombosis (P < 0.001). Of the patients with VTE treated with anticoagulation therapy (n = 147), 4.08% (n = 6) had bleeding. The VTE recurrence rate was 5.03% (n = 8). Patients with VTE treated by non-ultrasound-guided venous cannulation (P = 0.02), with residual thrombus (P = 0.006), or with short anticoagulation period (P = 0.026) had high recurrence rates. Thus, preventing repeated venous puncture and appropriately prolonged anticoagulation time can reduce the risk of VTE recurrence.

关键词： acute lymphoblastic leukemia     child     venous thromboembolism     epidemiology     clinical characteristic     risk factor    

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Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia

null

《医学前沿（英文）》 2015年 第9卷 第1期   页码 1-9 doi: 10.1007/s11684-015-0381-3

摘要：

With the cure rate of childhood acute lymphoblastic leukemia (ALL) approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future.

关键词： pharmacogenomics     acute lymphoblastic leukemia     genomics     pharmacogenetics    

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Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse largeB-cell lymphoma in Chinese patients

《医学前沿（英文）》 2022年 第16卷 第2期   页码 285-294 doi: 10.1007/s11684-021-0843-8

摘要： Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade≥3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.

关键词： CAR-T cell therapy     refractory diffuse large B-cell lymphoma     cytokine release syndrome     dose-limiting toxicity    

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年 第15卷 第6期   页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells     hematological malignancies     review    

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供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病 Article

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

《工程（英文）》 2019年 第5卷 第1期   页码 150-155 doi: 10.1016/j.eng.2018.12.006

摘要：

白血病复发仍是异基因造血干细胞移植（allogeneic hematopoietic stem cell transplantation，allo-HSCT）后急性B 淋巴细胞白血病（B cellacute lymphoblastic leukemia，B-ALL）治疗失败的主要原因。allo-HSCT 后B-ALL 复发患者的中位生存期很短。HSCT 后治疗伴有MRD 的B-ALL 的主要方法是供者淋巴细胞输注（donor lymphoblastic infusion，DLI）。无患者出现急性移植物抗宿主病（acute graft-versus-host disease，aGVHD），也无患者死于细胞因子释放综合征。

关键词： 供体来源的CD19靶向T细胞输注     造血干细胞移植     急性B淋巴细胞白血病     微小残留病    

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Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition)

《医学前沿（英文）》 2022年 第16卷 第5期   页码 815-826 doi: 10.1007/s11684-021-0891-0

摘要： Oral drugs such as ibrutinib play an important role in the treatment of mature B-cell lymphoma (BCL) due to their reliable efficacy, manageable safety, high accessibility, and convenience for use. Still, no guidelines or consensus focusing on oral drug therapies for BCL is available. To provide a reference of oral agent-based treatment for mature BCL, a panel of experts from the Lymphocyte Disease Group, Chinese Society of Hematology, Chinese Medical Association conducted an extensive discussion and reached a consensus on oral drugs for Chinese BCL patients on the basis of the current application status of oral drugs in China, combined with the latest authoritative guidelines in the world and current research reports. This consensus reviewed the application of oral drugs in the treatment of BCL and the latest research and provided appropriate recommendations on the use of oral drugs for indolent or aggressive BCL patients. With the deepening of research and the development of standardized clinical applications, oral medications will bring better treatment to BCL patients, enabling more patients to benefit from them.

关键词： B-cell lymphoma     oral drug     targeted therapy     immunotherapy     COVID-19 pandemic    

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imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acutelymphoblastic leukemia

null

《医学前沿（英文）》 2017年 第11卷 第2期   页码 229-238 doi: 10.1007/s11684-017-0506-y

摘要：

A CALLG2008 protocol was developed by the Chinese Acute Lymphoblastic Leukemia Cooperative Group for adult acute lymphoblastic leukemia (ALL). We retrospectively analyzed 153 newly diagnosed adult patients with Philadelphia chromosome (Ph)-positive ALL enrolled into imatinib (400 mg/d) plus CALLG2008 regimen between 2009 and 2015. The median age was 40 years (range, 18–68 years), with 81 (52.3%) males. The overall hematologic complete remission (CR) rate was 96.7% after induction. With a median follow-up of 24.2 months, the estimated 3-year overall survival (OS) and event-free survival (EFS) rates were 49.5% (95% confidence interval (CI): 38.5%–59.5%) and 49.2% (95% CI: 38.3%–59.2%), respectively. Fifty-eight (36 with haploidentical donor) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first CR. Among the patients in CR1 after induction, both the 3-year OS and EFS were significantly better in the allo-HSCT group than in the without allo-HSCT group (73.2%, 95% CI: 58.3%–83.5% vs. 22.2%, 95% CI: 8.7%–39.6% and 66.5%, 95% CI: 50.7%–78.2% vs. 16.1%, 95% CI: 5.1%–32.7%, respectively). Multivariate analysis showed that allo-HSCT and achievement of major molecular response were associated with favorable OS or EFS independently. Interestingly, in the allo-HSCT cohort, the donor type (haploidentical versus matched donors) had no significant impact on EFS or OS. All these results suggested that imatinib plus CALLG2008 was an effective protocol for Ph-positive ALL. Haploidentical donors can also be a reasonable alternative expedient donor pool.

关键词： Philadelphia chromosome     acute lymphoblastic leukemia     imatinib     CALLG2008    

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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

《医学前沿（英文）》 2023年 第17卷 第4期   页码 699-713 doi: 10.1007/s11684-022-0972-8

摘要： Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

关键词： anti-CD19 chimeric antigen receptor T     immunotherapy     diffuse large B cell lymphoma     tumor microenvironment     tumor-associated macrophage     metabolism    

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Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse

null

《医学前沿（英文）》 2015年 第9卷 第4期   页码 412-420 doi: 10.1007/s11684-015-0423-x

摘要：

Genetic mutations are considered to drive the development of acute myeloid leukemia (AML). With the rapid progress in sequencing technologies, many newly reported genes that are recurrently mutated in AML have been found to govern the initiation and relapse of AML. These findings suggest the need to distinguish the driver mutations, especially the most primitive single mutation, from the subsequent passenger mutations. Recent research on DNA methyltransferase 3A (DNMT3A) mutations provides the first proof-of-principle investigation on the identification of preleukemic stem cells (pre-LSCs) in AML patients. Although DNMT3A mutations alone may only transform hematopoietic stem cells into pre-LSCs without causing the full-blown leukemia, the function of this driver mutation appear to persist from AML initiation up to relapse. Therefore, identifying and targeting preleukemic mutations, such as DNMT3A mutations, in AML is a promising strategy for treatment and reduction of relapse risk.

关键词： preleukemic stem cell     acute myeloid leukemia     relapse     DNMT3A    

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

《医学前沿（英文）》 2020年 第14卷 第6期   页码 701-710 doi: 10.1007/s11684-020-0763-z

摘要： Abstract Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

关键词： acute myeloid leukemia     CAR T     immunotherapy    

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标题 作者 时间 类型 操作

characterization and comparison between CD3/CD19 bispecific and novel CD3/CD19/CD20 trispecific antibodies against B-cellacute lymphoblastic leukemia: targeted immunotherapy for acute lymphoblastic leukemia

期刊论文

Emerging molecular subtypes and therapeutic targets in B-cell precursor acute lymphoblastic leukemia

Jianfeng Li, Yuting Dai, Liang Wu, Ming Zhang, Wen Ouyang, Jinyan Huang, Saijuan Chen

期刊论文

Early T-cell precursor leukemia: a subtype of high risk childhood acute lymphoblastic leukemia

null

期刊论文

Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia

期刊论文

Precision medicine in acute lymphoblastic leukemia

Ching-Hon Pui

期刊论文

Venous thromboembolism in children with acute lymphoblastic leukemia in China: a report from the Chinese

期刊论文

Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia

null

期刊论文

Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse largeB-cell lymphoma in Chinese patients

期刊论文

CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

期刊论文

供体来源的CD19靶向T细胞输注可以消除异基因造血干细胞移植后对供者淋巴细胞无反应的急性B淋巴细胞白血病微小残留病

程翼飞, 陈育红, 闫晨华, 王昱, 赵翔宇, 陈瑶, 韩伟, 许兰平, 张晓辉, 刘开彦, 王莎莎, 张隆基, 肖磊, 黄晓军

期刊论文

Chinese expert consensus on oral drugs for the treatment of mature B-cell lymphomas (2020 edition)

期刊论文

imatinib plus CALLG2008 protocol in adult patients with newly diagnosed Philadelphia chromosome-positive acutelymphoblastic leukemia

null

期刊论文

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma

期刊论文

Mutant DNA methylation regulators endow hematopoietic stem cells with the preleukemic stem cell property, a requisite of leukemia initiation and relapse

null

期刊论文

Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

期刊论文