NEJM:首个报道!CAR-T让这种淋巴瘤的脑转移完全缓解
2017/09/04
首个产品正式获美国FDA批准、吉利德以119亿美元收购Kite Pharma,8月底的这两个重磅事件将CAR-T疗法的2017年推向了新的高潮。近日,麻省总医院联合Juno Therapeutics在NEJM杂志上公布了一项CAR-T疗法的临床结果。这是关于在中枢神经系统淋巴瘤中对CAR-T疗法响应的首个报道。


图片来源:网络

8月24日,在给NEJM杂志的一封信中(题目:Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma),来自麻省总医院(MGH)的一个研究小组报告了一名参与CAR-T疗法临床试验的患者出现的显著治疗响应:用CAR-T疗法治疗诱导了难治性弥漫性大B细胞淋巴瘤(diffuse large-B-cell lymphoma,DLBCL)脑转移的完全缓解。这是关于在中枢神经系统淋巴瘤中对CAR-T疗法响应的首个报道。

报道还称,当CAR-T治疗两个月后一处皮下肿瘤复发时,在进行了活检后,CAR-T细胞竟然会自发地重新扩增,肿瘤再次进入缓解。这一现象先前从未被报道过。虽然患者最终在CAR-T治疗一年多后死亡,但脑部肿瘤从未复发。

MGH癌症中心的Jeremy Abramson博士解释称:“DLBCL脑转移的预后极差,常规疗法诱导如此完全和持久响应的能力是罕见的。”

不同于传统药物,CAR-T疗法是从患者体内分离出T细胞,在体外对T细胞进行改造,为其装上能够特异性识别癌细胞的“导航”——嵌合抗原受体(CAR)后,再将这类“改装后的CAR-T细胞”进行扩增,回输到患者体内,发挥特异的抗癌作用。

这一临床试验由Juno Therapeutics公司发起,旨在测试其靶向CD19的CAR-T疗法JCAR017。CD19在大多数B细胞白血病和淋巴瘤中都有表达。DLBCL是一种侵袭性癌症,能够在多种组织中发展。

被报道的这名患者是一位68岁的女性。她患有的DLBCL对常规化疗或干细胞移植都不响应。这种情况通常会导致患者预期寿命不到6个月。当被招募进入调查JCAR017安全性和抗肿瘤活性的1期临床试验中时,医生发现她的大脑右颞叶有新的病灶。


Pretreatment and Post-treatment Imaging.(图片来源:NEJM)

报道称,治疗一个月后(化疗后JCAR017静脉注射),随访成像显示,大脑病灶完全缓解了。两个月后复发的皮下病灶在活检后也消失了,并且这种消失是发生在没有进一步治疗的情况下。(The subcutaneous lesion that recurred two months later disappeared after the biopsy with no further treatment.)血液检测显示,与肿瘤消退一致的是,患者体内CAR-T细胞的数量增加了。

Abramson博士说:“通常,我们用来对抗癌症和其它疾病的药物会随着时间的推移而逐渐消失。这种活检后自发的重新增殖表明,CAR-T疗法是完全不同的。这种‘活的药物’能够响应生物刺激,进而重新增殖。”科学家们认为,弄清CAR-T细胞重新激活背后的机制有望进步一增强这类疗法的功效。

参考资料:

Team reports first response of central nervous system tumor to CAR T-cells

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  • Anti-CD19 CAR T Cells in CNS Diffuse Large-B-Cell Lymphoma

    We report the case of a 68-year-old woman with refractory diffuse large-B-cell lymphoma (DLBCL), germinal-center subtype, with a BCL2 rearrangement and multiple copies of MYC and BCL6. Her disease was refractory to intensive infusional chemotherapy, dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R), and then to four additional lines of therapy, including intermediate-intensity allogeneic stem-cell transplantation from an 8/8 HLA-matched unrelated donor. She enrolled in a clinical trial of JCAR017 (ClinicalTrials.gov number, NCT02631044), a CD19-directed chimeric antigen receptor (CAR) T-cell product. At the time of enrollment, she had 100% donor chimerism in all blood lineages and was not receiving immunosuppressive therapy. She did not have graft-versus-host disease (GVHD). She underwent apheresis and disease restaging immediately before CAR T-cell therapy, at which time she had a new right-temporal-lobe brain lesion on positron-emission tomography and computed tomography (PET-CT) (Figure 1AFIGURE 1 Pretreatment and Post-treatment Imaging.), which was confirmed by magnetic resonance imaging (MRI) (Figure 1C). She received lymphodepleting fludarabine–cyclophosphamide, followed by JCAR017. No cytokine release syndrome, neurotoxic effects, or GVHD was observed. Restaging PET-CT (Figure 1B) and brain MRI (Figure 1D) 1 month later showed complete remission. Two months later, restaging scans showed recurrent subcutaneous disease (Figure 1E). After incisional biopsy, the visible tumor receded with no further therapy. Pharmacokinetic testing showed a marked expansion of CAR T cells (see the Supplementary Appendix, available with the full text of this letter at NEJM.org), which coincided with tumor regression. Restaging PET-CT 1 month after the biopsy confirmed complete remission (Figure 1F).

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