经常认为，复发/难治大B细胞淋巴瘤（r/r LBCL）中，CD19定向的嵌合抗原受体T细胞（CAR-T）后复发是由于抗原丢失或CAR-T疲劳所致。多抗原靶向和PD-1阻断是防止复发的合理方法。在此，我们测试了CD19/22双靶向CAR-T（AUTO3）再加上Pembrolizumab作为住院或门诊治疗r/r LBCL（NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455）。终点包括毒性（主要）和响应率（次要）。使用自体淋巴细胞分离制造了62名患者的AUTO3，经双元转基因修饰。52名患者接受了AUTO3（7/52,50x106; 45/52,150-450x106），48/52接受了Pembrolizumab。中位年龄为59岁（范围为27-83岁），46/52患有III/IV期疾病。截至最后的数据截止日期（2022年2月28日），中位随访时间为21.6个月（范围为15.1-51.3个月）。 AUTO3安全：18/52（34.6%）和1/52（1.9%）患者受到1-2级和3级CRS的影响，神经毒性在4名患者中出现（2/4，3-4级），2名患者发生了HLH，没有观察到Pembrolizumab相关的自身免疫后遗症。基于此，门诊治疗在20名患者中进行了测试，每名患者节省了14天的住院时间。 AUTO3有效：总体响应率为66%（48.9% CR；17% PR）。对于CR患者，中位DOR尚未确定，预计有54.4%（CI：32.8,71.7）在缓解开始后12个月内保持无进展。对于所有有响应的患者，DOR为8.3个月（95% CI：3.0，NE），预计有42.6%在缓解开始后12个月内保持无进展。总之，对于r/r LBCL，AUTO3+/- Pembrolizumab是安全的，适合进行门诊治疗，并且在54.4%的完全缓解者中提供了持久的缓解，与强大的CAR-T扩张相关。双靶向CAR-T和Pembrolizumab都没有在相当比例的患者中防止复发，未来的发展包括下一代-AUTO3，该治疗仍需要更开发出活力更高/更持久的CAR重组抗体和低抗原密度的CAR结合物选择。 版权所有 © 2023美国血液学会。

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.Copyright © 2023 American Society of Hematology.