Department of Haematology, Aalborg University Hospital, Aalborg, Denmark.
Clinical Cancer Research Centre, Aalborg University Hospital, Aalborg, Denmark.
Acta Oncol. 2020 Jul;59(7):766-774. doi: 10.1080/0284186X.2020.1741680. Epub 2020 Mar 19.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype. Disease progression or relapse following frontline chemoimmunotherapy, largely in the form of standard R-CHOP, occurs in 30-40% patients. Relapsed/refractory (R/R) DLBCL represents a major unmet medical need. In particular, patients with primary refractory disease or those whose lymphoma relapses after autologous stem cell transplantation have historically had poor outcomes. Chimeric antigen receptor T-cell (CART) therapy is a promising novel treatment with curative potential in this setting. CART is based on genetic modification of autologous T-cells to express chimeric receptors targeting antigens highly expressed in tumors such as CD19 in DLBCL. After lymphocyte-depleting therapy, patients are infused with CARTs that expand and target CD19-positive lymphoma cells. In initial phase I-II trials, investigators have demonstrated complete responses in 40-50% of patients with R/R DLBCL, resulting in durable remission approaching 3 years of follow-up in most of these patients without further treatment. The logistics of delivery are complex as cell products require timely long-distance transfer between hospitals and production facilities. The unique toxicity profile of CARTs, including the risk of fatal immunological and neurologic events, also requires specific hospital wide management approaches and education. The substantial direct and indirect costs of CART will limit access even in countries with well resourced health care systems. While only two products are commercially available at present, further approvals in coming years appear likely. Future directions include CARTs with reactivity to tumor antigens other than CD19 and products targeting multiple tumor antigens to overcome resistance. The availability of CART has altered the current treatment algorithm for R/R DLBCL, and indications will likely expand to earlier lines of therapy and other hematologic malignancies.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的淋巴瘤亚型。在一线化疗免疫治疗后，约 30-40%的患者出现疾病进展或复发，主要形式为标准 R-CHOP。复发/难治性（R/R）DLBCL 代表了一个重大的未满足的医疗需求。特别是那些原发性难治性疾病的患者或那些在自体干细胞移植后淋巴瘤复发的患者，其历史预后较差。嵌合抗原受体 T 细胞（CART）疗法是一种很有前途的新型治疗方法，在这种情况下具有潜在的治愈能力。CART 基于对自体 T 细胞进行基因修饰，使其表达针对肿瘤中高度表达的抗原的嵌合受体，如 DLBCL 中的 CD19。在淋巴细胞耗竭治疗后，患者输注 CART，CART 会扩增并靶向 CD19 阳性淋巴瘤细胞。在最初的 I-II 期试验中，研究人员在 R/R DLBCL 患者中观察到 40-50%的患者完全缓解，在大多数患者中没有进一步治疗，随访 3 年以上可达到持久缓解，没有进一步治疗。由于细胞产品需要在医院和生产设施之间及时进行长途转移，因此其物流配送非常复杂。CART 独特的毒性特征，包括致命性免疫和神经事件的风险，也需要特定的医院管理方法和教育。即使在医疗资源充足的国家，CART 的巨额直接和间接成本也将限制其获得。虽然目前只有两种产品可商业化，但未来几年可能会有更多的批准。未来的方向包括对 CD19 以外的肿瘤抗原具有反应性的 CART 和针对多个肿瘤抗原的产品，以克服耐药性。CART 的出现改变了 R/R DLBCL 的当前治疗方案，适应证可能会扩展到更早的治疗线和其他血液恶性肿瘤。
