【前沿】嵌合抗原受体修饰T细胞免疫疗法（CART）对白血病疗效显著

关键信息

本研究中，25例复发性急性淋巴细胞白血病（ALL）患儿与5例成年患者接受CD19定向嵌合抗原受体（CTL019）慢病毒载体输注治疗。这些患者中，27例达到完全缓解。共计19例患者在2~24个月的随访期内持续缓解。患者总生存率为78%，6个月无事件生存率为67%。尽管有27%的患者出现严重的细胞因子释放综合征，但均成功治疗。

有复发史的患儿与成年患者在接受CD19靶向嵌合抗原受体修饰T细胞治疗后，病情持续缓解，其中部分患者曾有不成功的干细胞移植治疗史。

专家评述

 

急性淋巴细胞白血病（ALL）是一种侵袭性恶性肿瘤，其发病率与死亡率都很高，对于难治性或复发性患者尤其如此。ALL领域的进展主要表现在3个方面：①针对费城（Ph）染色体阳性以及Ph样ALL的酪氨酸激酶抑制剂；②较新的药物包括达沙替尼和帕纳替尼。③结合或不结合细胞表面标记物的单克隆抗体的发展，包括利妥昔单抗（靶向CD20），奥法木单抗（靶向CD20），inotuzumab 单抗（靶向CD22），双特异性抗体blinatumomab（靶向宿主CD3 T细胞和CD19肿瘤B细胞），以及针对B细胞抗原的嵌合抗原受体T细胞（CART）治疗（CTL019，之前也被称为CART19）。

嵌合型抗原受体（CAR）通过将抗CD19单链Fv区域与T细胞受体的细胞内T细胞信号区相结合，由基因工程产生，因而能将细胞毒性T淋巴细胞再定向于表达CD19的细胞（肿瘤B细胞，即ALL细胞）。通过应用慢病毒基因转移技术，对细胞毒性T细胞进行永久性修饰，因此，该治疗效果可持续，克服了目前基于细胞的治疗的难点。

Maude 等已经证实CART19对30例复发性/难治性B细胞ALL患者（25例为儿童）有显著疗效。这些患者中，有27例（90%）达到完全缓解，多数为持续性（24个月）。6个月无事件生存率达67%，而总生存率为78%。有3例患者此前为blinatumomab难治性患者，18例患者在此前接受异体干细胞移植后有复发。2例在脑脊液（CFS）中可检测到肿瘤细胞的中枢神经系统（CNS）疾病患者，在CART治疗后疾病消除，重要的是，在随访期内，该组患者无CNS复发。主要的不良反应包括细胞因子释放综合征（所有患者均有一定程度的表现）、脑病和延迟性B细胞再生障碍。

27%的患者有严重的细胞因子释放综合征，使用托珠单抗（tocilizumab，一种IL-6受体阻断抗体）联合或不联合皮质类固醇即可有效控制。延迟性B细胞再生障碍见于所有患者，采用静脉注射丙种球蛋白替代治疗。复发或与CTL019持续性缺乏相关，或与CD19免疫逃避突变相关。

总之，CART治疗对复发性/难治性B细胞ALL患者的管理是非常有效的策略。在当下，该治疗可用于患者异体干细胞移植的过渡性治疗，或作为移植后疾病复发的挽救性方案。此外，这一技术让细胞治疗领域再次复苏，目前也正在探索其他靶点，如CD33和CD123，以便对侵袭性髓样肿瘤患者提供相似的治疗。

TAKE-HOME MESSAGE

In this study, 25 pediatric and 5 adult patients who had experienced relapses of acute lymphoblastic leukemia (ALL) were infused with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector. Of these patients, 27 achieved complete remission. A total of 19 patients maintained remission over the 2- to 24-month follow-up period. The overall survival rate was 78%, and the 6-month event-free survival rate was 67%. While 27% of patients developed severe cytokine-release syndrome, this was successfully treated.

Chimeric antigen receptor–modified T-cell therapy targeted against CD19 produced lasting remission in formerly relapsed pediatric and adult patients, some of whom had already undergone unsuccessful stem cell transplants.

Expert Comment

Mrinal S. Patnaik MBBS

Acute lymphoblastic leukemia (ALL) is an aggressive malignancy associated with high morbidity and mortality, especially pronounced in patients with refractory or relapsed disease. Advances in the field of ALL have occurred in three major directions:

Tyrosine kinase inhibitors for Philadelphia (Ph) chromosome–positive and Ph-like ALL; newer agents include dasatinib and ponatinib

Development of monoclonal antibodies with or without conjugates against cell surface markers

rituximab–CD20

ofatumumab–CD20

inotuzumab–antibody conjugate against CD22

blinatumomab–bispecific antibody engaging host T cells–CD3 with the neoplastic B cells–CD19

Development of chimeric antigen receptor T cells (CART) against B-cell antigens (CTL019; formerly known as CART19).

Chimeric antigen receptors (CAR) are genetically engineered by coupling the anti-CD19 single-chain Fv domain with the intracellular T-cell signaling domains of the T-cell receptor, thereby redirecting cytotoxic T lymphocytes to cells expressing CD19 (neoplastic B-ALL cells). By using lentiviral gene transfer technology, these modifications in the cytotoxic T cells are permanent, thus overcoming prior issues with sustainability of this kind of cell-based therapy.

Maude et al have demonstrated remarkable efficacy of CART19 therapy in 30 patients (25 pediatric) with relapsed/refractory B-ALL. Of these patients, 27 (90%) achieved a complete remission, with many of them being durable (24 months). The 6-month event-free survival was 67%, while the overall survival was 78%. There were 3 patients with prior refractoriness to blinatumomab, while 18 patients had relapsed after undergoing prior allogeneic stem cell transplants. The 2 patients who had CNS disease with detectable CSF blasts cleared this with CART therapy and, importantly, at last follow-up, no CNS relapses were seen in the study cohort. Major side effects included cytokine release syndrome (seen to some degree in all patients), encephalopathy, and prolonged B-cell aplasia.

Severe cytokine release syndrome was seen in 27% of patients and was effectively managed with tocilizumab (an IL-6 receptor–blocking antibody), with or without corticosteroids. Prolonged B-cell aplasia was seen in all patients and was managed with intravenous gamma globulin replacement. Relapses seen were associated with either lack of CTL019 persistence or CD19 escape variants.

In summary, CART therapy is a very effective strategy for the management of patients with relapsed/refractory B-ALL. In its current state, it can be used to bridge these patients toward allogeneic stem cell transplantation or as a salvage regimen in the setting of post-transplant disease relapse. Furthermore, this technology has reinvigorated the field of cell-based therapy, and additional targets such as CD33 and CD123 are being explored so as to offer similar therapies for patients with aggressive myeloid neoplasms.

The New England Journal of Medicine

Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

N. Engl. J. Med 2014 Oct 16;371(16)1507-1517, SL Maude, N Frey, PA Shaw, R Aplenc, DM Barrett, NJ Bunin, A Chew, VE Gonzalez, Z Zheng, SF Lacey, YD Mahnke, JJ Melenhorst, SR Rheingold, A Shen, DT Teachey, BL Levine, CH June, DL Porter, SA Grupp

This abstract is available on the publisher's site.

Access this abstract now

Copyright © 2014 Elsevier Inc. All rights reserved.

独家授权，未经许可，请勿转载。