CAR-T细胞治疗儿童白血病的研究进展

<正>近年来,作为一种革命性和颠覆性的细胞免疫治疗技术,嵌合抗原受体T细胞（chimeric antigen receptor T cell,CAR-T）治疗在复发、难治血液肿瘤领域取得了重大突破,目前已经逐渐成为复发、难治性儿童白血病的首选治疗方案。本文将总结CAR-T在儿童B系急性淋巴细胞白血病（B-lineage acute lymphoblastic leukemia,B-ALL）、T系急性淋巴细胞白血病（T-lineage acute lymphoblastic leukemia,T-ALL）和急性髓系白血病（acute myeloid leukemia,AML）的研究进展,并结合各自特点,讨论CAR-T治疗中一些亟待解决的问题,同时梳理CAR-T治疗的副作用和管理方案,旨在使CAR-T治疗更加安全高效。     

嵌合抗原受体-T细胞治疗儿童肿瘤的临床研究进展

儿童肿瘤患者的5年生存率已达80%以上,但仍有部分复发难治性肿瘤通过传统治疗手段难以取得理想疗效。嵌合抗原受体(CAR)-T细胞技术的发展为治愈这些肿瘤带来了希望。CAR-T细胞通过非MHC限制性的方式识别肿瘤相关抗原,抗肿瘤能力显著增强,目前已发展到第四代。靶向CD19的CAR-T细胞治疗复发难治性急性淋巴细胞白血病缓解率高达90%,且可以通过桥接造血干细胞移植、供者CAR-T细胞输注等手段辅助白血病的治疗。实体瘤方面,靶向GD2的CAR-T细胞治疗神经母细胞瘤具有良好的反应性,但对其他实体瘤效果欠佳。CAR-T细胞治疗可能出现细胞因子释放综合征、脱靶效应、肿瘤溶解综合征、插入突变等毒副反应。靶向CD19的CAR-T细胞治疗虽有很高的缓解率,但复发率较高,包括CD19~+和CD19~-复发,其机制尚需进一步研究。     

嵌合抗原受体-T细胞治疗急性髓系白血病靶点的研究

急性髓系白血病(AML)是血液系统的恶性肿瘤,复发和难治仍然是临床难题.嵌合抗原受体修饰T(CAR-T)细胞在B细胞恶性肿瘤已经取得令人鼓舞的结果,与CAR-T治疗B系肿瘤相比,针对AML的CAR-T细胞治疗临床试验相对较少,疗效也明显差于B系肿瘤.CAR-T成功应用于AML患者的最大挑战是选择有效且安全的抗原靶点.本...     

CAR-T细胞治疗在儿童白血病治疗中的应用

正白血病在儿童恶性肿瘤中的发病率占首位,严重威胁儿童生命和健康。儿童期白血病多为急性白血病,其中75%为急性淋巴细胞白血病(acute lymphoblastie leukemia,ALL),高发年龄在2～5岁[1]。化疗和异基因骨髓移植是儿童急性白血病的主要治疗手段,化疗效果虽然显著,但副作用较大,且对于高危和复发的病人疗效欠佳,而骨髓移植存在配型困难的问题,总体复发率为15%～20%[2-4]。因此,临床上仍需寻找新的治疗方法。近年来,嵌合抗原受体T细胞(chimeric antigen receptor T cells,CAR-T)在血液肿瘤治疗中的突出表现,使人们对白血病的     

CD19嵌合抗原受体T细胞治疗急性B淋巴细胞白血病移植术后复发一例

患儿男,7岁,因“确诊急性淋巴细胞白血病21个月余”入住解放军联勤保障部队第九六〇医院血液科,患儿行亲缘半相合造血干细胞移植,原发病获得完全缓解(CR)。移植术后11个月患儿出现睾丸复发,给予放疗,效果可。后出现骨髓复发,行化疗及供者淋巴细胞输注(DLI)等治疗无效,给予输注自体来源抗CD19嵌合抗原受体T细胞(CAR-T),患儿原发病获得CR。抗CD19的CAR-T细胞可作为治疗儿童急性B淋巴细胞白血病移植术后复发的重要手段。     

TRIP3基因与白血病细胞凋亡

白血病是造血系统常见的恶性肿瘤,而急性淋巴细胞白血病是小儿白血病中发病率最高的类型,占小儿白血病总数的70%～80%.虽然目前国际上著名的儿童急性淋巴细胞白血病治疗中心,急淋的治愈率约达80%,但其缓解后的复发仍是白血病治疗最为棘手的问题.     

儿童急性淋巴细胞白血病复发与基因突变相关性

急性淋巴细胞白血病是儿童恶性肿瘤中最常见的类型,急性淋巴细胞白血病复发仍然是治疗的难题.随着近几年关于儿童急性淋巴细胞白血病复发机制的研究逐渐深入,越来越多的基因异常已经被证实与儿童急性淋巴细胞白血病复发相关,包括IKZF1缺失、PRED1缺失、JAK突变、CREBBP突变、CEBPE突变、ARID5B突变等.该文重点综述以上基因突变对儿童急性淋巴细胞白血病复发的影响.     

儿童中枢神经系统急性淋巴细胞白血病诊治进展

儿童急性淋巴细胞白血病是可治愈性疾病,多数患儿经过系统化治疗可持续完全缓解,但仍有部分复发,其中中枢神经系统受累是导致患儿复发以及影响生存质量的重要原因之一。临床儿科医生对中枢神经系统急性淋巴细胞白血病的诊断、防治等相关进展应有所了解。     

CRLF2基因在儿童B系急性淋巴细胞性白血病中的研究进展

儿童急性淋巴细胞性白血病的危险分层可用以指导治疗和评估预后.但临床特征提示预后良好以及早期治疗反应良好的患者仍占复发和死亡患者很大一部分比例.因此,研究与复发相关的基因异常将有利于提高患儿的治愈率.CRLF2基因的异常表达与JAK变异、BCR/ABL1样信号、IKZF缺失相关,其高表达与儿童B系急性淋巴细胞性白血病高危复发及不良预后相关,但其预后价值尚有争议.该文阐述CRLF2基因在儿童B系急性淋巴细胞性白血病中的研究进展.     

CD 19靶向的嵌合抗原受体T细胞治疗儿童急性B淋巴细胞白血病孤立性睾丸复发2例及文献复习

报道苏州大学附属儿童医院血液肿瘤科于2019年5月及12月收治的2例CD 19靶向的嵌合抗原受体T(CD 19 CAR-T)细胞治疗的急性B淋巴细胞白血病(B-ALL)孤立性睾丸复发(ITR)患儿的诊疗经过及结果,探讨CD 19 CAR-T细胞治疗相较于传统放化疗的疗效,并对相关文献进行复...     

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children

Abstract

CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy has shown striking response in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, side-effects including cytokine release syndrome (CRS) and neurotoxicity can be fatal to patients. In this report, five patients with r/r B-ALL were treated with CD19CAR-T cells. Cytokine release syndrome experienced by four patients who achieved complete remission (CR) with minimal residual disease (MRD) negative. One patient who did not response to the treatment had no CRS. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2?weeks post infusion and managed properly with tocilizumab and/or steroids according to the “real-time” monitoring of a simple 6 Th1/Th2 cytokine pattern. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be safely administered for patients with relapsed and refractory leukemia under the “real-time” monitoring of a simple 6-cytokine pattern.     

嵌合抗原受体T淋巴细胞治疗神经母细胞瘤的研究进展

嵌合抗原受体T淋巴细胞(chimeric antigen receptor T lymphocyte,CAR-T)免疫治疗是近年来开始出现的一种新型肿瘤免疫治疗方法,目前已经在白血病、淋巴瘤等晚期癌症患者中应用,并取得一定疗效.神经母细胞瘤是儿童最常见的颅外恶性实体肿瘤之一,有超过一半的患者在确诊时已经发生了转移.目前高危患儿的预后较差,临床需要寻找新的治疗方法.该文总结了CAR-T的基本结构及优化发展,讨论了其在神经母细胞瘤中的治疗原理及风险,并展望了CAR-T在实体肿瘤中的治疗前景.     

氯法拉滨治疗儿童复发/难治性急性淋巴细胞性白血病的疗效分析

目的：探讨氯法拉滨应用于儿童复发/难治性急性淋巴细胞性白血病的疗效和不良反应。方法：26例复发/难治性急性淋巴细胞性白血病患儿接受氯法拉滨单药治疗,男22例,女4例,中位年龄9.5岁（4~17岁）。患儿均接受连续5 d静脉滴注氯法拉滨（52 mg/m2,每次超过2 h）,其中13例患儿接受连续2次氯法拉滨单药化疗,1例患儿接受连续3次氯法拉滨单药化疗。结果：26例患儿第1次氯法拉滨化疗后11例（42%）获完全缓解,7例（27%）获部分缓解,总有效率69%,8例（31%）未缓解。26例患儿中,13例继续给予第2次氯法拉滨化疗后11例（85%）获完全缓解,1例（8%）部分缓解,1例（8%）未缓解。其中1例患儿接受3次氯法拉滨化疗均获完全缓解。化疗的不良反应主要为中性粒细胞减少、感染、肝功能损害、胃肠道反应,无化疗相关死亡病例。结论：氯法拉滨治疗儿童复发/难治性急性淋巴细胞性白血病有一定疗效,不良反应可以耐受,是一种新的治疗选择。     

Durable remissions achieved with reinfusion of CD19-directed CAR-T despite failure to induce or maintain B-cell aplasia and single-center experience with reinfusion of tisagenlecleucel

CD19-directed chimeric antigen receptor T lymphocytes (CAR-T) have led to durable remissions in children with refractory and/or multiply relapsed B-lymphoblastic leukemia. For those who relapse or lose B-cell aplasia post CAR-T, the role of CAR-T reinfusion is unclear. We report two cases of durable remission with tisagenlecleucel reinfusion despite failure to achieve or maintain B-cell aplasia, and compare these cases to six additional children who received multiple tisagenlecleucel infusions at our institution. Our experience suggests that reinfusion is safe and may be a definitive therapy for a small subset of patients. Reinfusion can also reintroduce remission and/or B-cell aplasia, allowing for subsequent therapies.     

Bone marrow transplantation improves survival for acute lymphoblastic leukemia in relapse: a preliminary report

Acute lymphoblastic leukemia of childhood is the most common malignant disease in children greater than 1 year of age. Chemotherapy has improved the survival of children with this disorder. More than 95% of children will achieve a remission with chemotherapy. However, 30% of children with acute lymphoblastic leukemia who achieved a remission will have a relapse sometime after successful remission-inducing chemotherapy. Although a second remission can be induced in most of these children, in 10-40% a remission cannot be induced or they relapse shortly thereafter and develop refractory leukemia. We present in this preliminary report the early results of therapy for refractory leukemia with an intensive preparative regimen for bone marrow transplantation including etoposide, cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Transplantation was done in twenty-three patients with refractory leukemia. Projected survival at 917 days after transplantation in these patients is 43.4% +/- 11%. The survival of these patients so far is similar to the survival of children with acute lymphoblastic leukemia transplanted in second remission. All patients treated with this regimen who had transplantation in relapse were free of leukemia 27 days after transplantation. The results of this preliminary report suggest that an intensive preparative regimen can improve the outlook of refractory leukemia and may rescue some patients who otherwise would have died of their disease.     

Acute lymphoblastic leukemia

Acute leukemia is the most common childhood malignancy, representing 30% of all cancer in American children under the age of 15 years and 12% of cancer cases in those ages 15 to 19 years old. In the United States, approximately 2500 new cases are diagnosed annually; 80% of these are acute lymphoblastic leukemia, 15% are acute myelogenous leukemia, and 5% belong to the chronic leukemia category.(1) The survival rates of children with acute leukemia have increased dramatically in the last 40 years.(2-5) The most success in outcome has occurred in acute lymphoblastic leukemia, although improvement is also being reported in acute myelogenous leukemia in the past few years. Progress comes from treatment strategy modifications on the basis of observations made in sequential large-scale therapeutic trials, an approach that serves as a paradigm for research in other malignant diseases.     

Chimeric antigen receptor T‐cell therapy in patients with neurologic comorbidities

Chimeric antigen receptor T cells (CAR‐T) are an effective and potentially durable treatment for refractory and multiply relapsed B‐cell acute lymphoblastic leukemia. Neurotoxicity is frequent after CAR‐T cell therapy. Mechanisms driving neurotoxicity are incompletely understood, and symptoms can range from transient and mild to severe and life‐threatening. Providers have exercised caution in providing CAR‐T to patients with neurological comorbidities or extramedullary disease. Here, we report three patients with prior significant neurologic morbidity who safely tolerated CAR‐T cell infusion after bridging therapy with conventional chemotherapy.     

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目的分析髓系抗原阳性儿童急性淋巴细胞白血病(ALL)的临床特点及预后关系。方法根据国际白血病欧洲协作组(EGIL)标准将1999—2004年上海交通大学医学院附属上海儿童医学中心收治的33例髓系抗原阳性表达的ALL(My+ALL)分为双表型、双系列型给予正规治疗。对其预后进行观察。结果(1)My+ALL患儿,双表型26例(78.8%,26/33),其中B系ALL伴髓系表达17例(65.4%,17/26),T系ALL伴髓系表达6例(23.1%,6/26),T系B系伴髓系表达3例(11.5%,3/26)。双系列ALL患儿7例(21.2%,7/33)。(2)26例双表型ALL患儿治疗35d,缓解率80.7%。7例双系列型ALL仅1例达缓解(14.3%)。(3)生存状态双表型26例中20例处于缓解状态(76.9%),双系列型7例中仅1例(14.3%)。(4)复发情况双表型6例复发(23.1%,6/26),双系列7例中6例复发(85.7%)。结论髓系抗原阳性表达在儿童ALL时不能作为预后不良的因素,但双系列白血病患儿预后差,复发率高,长期生存机会少。     

Psychosocial care for children receiving chimeric antigen receptor (CAR) T‐cell therapy

Chimeric antigen receptor (CAR) T‐cell therapy has transformed the treatment of relapsed/refractory B‐cell acute lymphoblastic leukemia (ALL). However, this new paradigm has introduced unique considerations specific to the patients receiving CAR T‐cell therapy, including prognostic uncertainty, symptom management, and psychosocial support. With increasing availability, there is a growing need for evidence‐based recommendations that address the specific psychosocial needs of the children who receive CAR T‐cell therapy and their families. To guide and standardize the psychosocial care offered for patients receiving CAR T‐cell therapy, we propose the following recommendations for addressing psychosocial support.