Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH Building 10 room 3-3330, Bethesda, Maryland 20892, USA.
Nat Rev Clin Oncol. 2018 Jan;15(1):31-46. doi: 10.1038/nrclinonc.2017.128. Epub 2017 Aug 31.
New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy-refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and κ-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies.
需要为对标准疗法耐药的霍奇金或非霍奇金淋巴瘤患者开发新的治疗方法。事实上，对标准化疗无反应和自体干细胞移植后复发是预后特别差的指标。嵌合抗原受体 (CAR) T 细胞作为这些患者的一种新的治疗方法正在出现。临床试验数据表明，抗 CD19 CAR T 细胞对多种 B 细胞淋巴瘤亚型具有强大的活性，包括弥漫性大 B 细胞淋巴瘤 (DLBCL)、滤泡性淋巴瘤、套细胞淋巴瘤和边缘区淋巴瘤。重要的是，抗 CD19 CAR T 细胞对化疗耐药的淋巴瘤具有显著的活性，在一些难治性 DLBCL 患者中诱导持续 2 年以上的持久完全缓解。然而，CAR-T 细胞疗法与潜在的致命毒性相关，包括细胞因子释放综合征和神经毒性。目前正在临床试验中研究针对 B 细胞淋巴瘤的新型靶抗原（包括 CD20、CD22 和 κ 轻链）和针对霍奇金和 T 细胞淋巴瘤的 CD30 的 CAR T 细胞。正在进行的行业赞助多中心临床试验也在测试中心制造的 CAR T 细胞，并且可能很快成为一种标准疗法。在此，我们综述了 CAR-T 细胞疗法治疗淋巴瘤的临床疗效和毒性，并讨论了它们在毒性管理、CAR 设计和 CAR-T 细胞表型、预处理方案和联合治疗方面的局限性和未来方向。
