Several second- and third-line immunotherapeutic options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant are directed against the B-cell antigen CD19. The anti-CD19 monoclonal antibody tafasitamab, paired with the immunomodulator lenalidomide, mediates antibody-dependent cellular toxicity and cellular phagocytosis; the antibody–drug conjugate loncastuximab tesirine delivers the DNA-cross-linking agent tesirine via CD19 binding and internalization; and CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) products are engineered from autologous T cells. While CD19 expression is assessed at diagnosis, clinically relevant thresholds of CD19 expression—which may not be detectable with current routine methodologies—have not been defined and may vary between CD19-directed treatment modalities. Determining optimal treatment sequencing strategies with CD19-directed therapy has been hampered by the exclusion of patients with prior CD19-directed therapies from major clinical trials. Antigen escape, attributed to mechanisms including epitope loss and defective cell-surface trafficking of CD19, is an important cause of CAR-T failure. Limited data suggest that CD19 expression may be maintained after non-CAR-T CD19-directed therapy and retrospective analyses indicate that some patients with disease that relapses after CAR-T may benefit from subsequent CD19-directed therapy. To date, clinical evidence on the effect of anti-CD19 therapy prior to CAR-T is restricted to small case series. Prospective studies and detailed analyses to understand how pre- and post-treatment CD19 expression correlates with clinical responses to subsequent CD19-directed therapy are needed to fully maximize treatment strategies.

中文翻译：

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弥漫性大 B 细胞淋巴瘤治疗中抗 CD19 疗法的测序

对于不适合自体干细胞移植的复发或难治性弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者，有几种二线和三线免疫治疗选择针对 B 细胞抗原 CD19。抗CD19单克隆抗体tafasitamab与免疫调节剂来那度胺配对，介导抗体依赖性细胞毒性和细胞吞噬作用；抗体-药物偶联物 loncastuximab tesirine 通过 CD19 结合和内化传递 DNA 交联剂 tesirine； CD19定向嵌合抗原受体T细胞疗法（CAR-T）产品是由自体T细胞改造而成。虽然在诊断时评估 CD19 表达，但目前常规方法可能无法检测到的 CD19 表达的临床相关阈值尚未确定，并且可能因 CD19 导向的治疗方式而异。由于将先前接受过 CD19 定向治疗的患者排除在主要临床试验之外，因此阻碍了确定 CD19 定向治疗的最佳治疗测序策略。由于表位丢失和 CD19 细胞表面运输缺陷等机制导致的抗原逃逸是 CAR-T 失败的重要原因。有限的数据表明，非 CAR-T CD19 定向治疗后 CD19 表达可能得以维持，回顾性分析表明，一些 CAR-T 后疾病复发的患者可能会受益于后续的 CD19 定向治疗。迄今为止，关于 CAR-T 之前抗 CD19 治疗效果的临床证据仅限于小病例系列。需要进行前瞻性研究和详细分析，以了解治疗前和治疗后 CD19 表达与后续 CD19 定向治疗的临床反应如何相关，以充分最大化治疗策略。