Despite recent advances in frontline therapy for diffuse large B-cell lymphoma (DLBCL), at least a third of those diagnosed still will require second or further lines for relapsed or refractory (rel/ref) disease. A small minority of these can be cured with standard chemoimmunotherapy/stem-cell transplant salvage approaches. CD19-directed chimeric antigen receptor T-cell (CAR-19) therapies are increasingly altering the prognostic landscape for rel/ref patients with DLBCL and related aggressive B-cell non-Hodgkin lymphomas. Long-term follow up data show ongoing disease-free outcomes consistent with cure in 30–40% after CAR-19, including high-risk patients primary refractory to or relapsing within 1 year of frontline treatment. This has made CAR-19 a preferred option for these difficult-to-treat populations. Widespread adoption, however, remains challenged by logistical and patient-related hurdles, including a requirement for certified tertiary care centers concentrated in urban centers, production times of at least 3–4 weeks, and high per-patients costs similar to allogeneic bone-marrow transplantation. Bispecific antibodies (BsAbs) are molecular biotherapies designed to bind and activate effector T-cells and drive them to B-cell antigens, leading to a similar cellular-dependent cytotoxicity as CAR-19. May and June of 2023 saw initial approvals of next-generation BsAbs glofitamab and epcoritamab in DLBCL as third or higher-line therapy, or for patients ineligible for CAR-19. BsAbs have similar spectrum but generally reduced severity of immune related side effects as CAR-19 and can be administered in community settings without need to manufacture patient-specific cellular products. To date and in contrast to CAR-19, however, there is no convincing evidence of cure after BsAbs monotherapy, though follow up is limited. The role of BsAbs in DLBCL treatment is rapidly evolving with trials investigating use in both relapsed and frontline curative-intent combinations. The future of DLBCL treatment is bound increasingly to include effector cell mediated immunotherapies, but further optimization of both cellular and BsAb approaches is needed.
尽管弥漫大B细胞淋巴瘤（DLBCL）的一线治疗近期取得进展，但确诊患者中仍有至少三分之一因复发或难治性疾病需要接受二线或后续治疗。其中极少数患者可通过标准化疗免疫治疗/干细胞移植挽救方案获得治愈。CD19靶向嵌合抗原受体T细胞（CAR-19）疗法正日益改变DLBCL及相关侵袭性B细胞非霍奇金淋巴瘤复发或难治患者的预后格局。长期随访数据显示，CAR-19治疗后30%-40%的患者（包括对一线治疗原发耐药或一年内复发的高危患者）获得持续无病生存，这符合临床治愈标准。因此CAR-19已成为这类难治群体的优选方案。然而，该疗法的广泛应用仍面临物流和患者相关障碍的挑战，包括：需集中在城市认证的三级医疗中心实施、至少3-4周的生产制备周期、以及与异基因骨髓移植相当的高昂人均治疗成本。
双特异性抗体（BsAbs）是通过结合并激活效应T细胞、驱动其靶向B细胞抗原的分子生物疗法，能产生与CAR-19类似的细胞依赖性细胞毒性。2023年5月和6月，新一代双特异性抗体glofitamab与epcoritamab首次获批用于DLBCL的三线及以上治疗，或适用于不符合CAR-19治疗条件的患者。双特异性抗体与CAR-19的免疫相关副作用谱相似但严重程度通常较低，且可在基层医疗机构实施，无需制备患者特异性细胞产品。但迄今为止，与CAR-19形成对比的是，虽随访数据有限，尚无双特异性抗体单药治疗可达到治愈的确凿证据。双特异性抗体在DLBCL治疗中的应用正通过复发性和一线治愈性联合疗法的临床试验快速发展。DLBCL治疗的未来必将越来越多地包含效应细胞介导的免疫疗法，但细胞疗法与双特异性抗体方案均需进一步优化。
Bispecific antibodies and CAR-T cells: dueling immunotherapies for large B-cell lymphomas
肿瘤(癌症)患者之家