肿瘤细胞治疗研究
英文原题：Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients.
CAR19 T细胞用于治疗复发/难治性儿童B细胞急性淋巴细胞白血病（ALL；n = 31）或成人B细胞淋巴瘤（NHL；
靶向CD19抗原的嵌合抗原受体（CAR）T细胞可有效治疗成人和儿童B细胞恶性肿瘤。床旁生产可能通过免除冷冻保存和将细胞运输至集中式设施的需要来提高性能和可及性。在此，我们开发了一种抗CD19 CAR（CAR19），由4-1BB共刺激结构域和TNFRSF19跨膜结构域组成，在体内异种移植淋巴瘤模型中显示出抗肿瘤疗效。CAR19 T细胞在两个不同的临床中心（俄罗斯莫斯科和美国克利夫兰）按照现行药品生产质量管理规范（cGMP）生产。CAR19 T细胞用于治疗复发/难治性儿童B细胞急性淋巴细胞白血病（ALL；n = 31）或成人B细胞淋巴瘤（NHL；n = 23）患者，在两项独立进行的I期临床试验中，以安全性为主要结局（分别为NCT03467256和NCT03434769）。可测量残留病灶阴性缓解的概率也是ALL研究的主要结局。次要结局包括完全缓解（CR）率、总生存期和缓解持续时间中位数。CR率分别为89%（ALL）和73%（NHL）。中位随访17个月后，ALL完全缓解者的一年生存率为79.2%（95%CI 64.5-97.2%），缓解持续时间中位数为10.2个月。对于NHL完全缓解者，一年生存率为92.9%，缓解持续时间中位数尚未达到。床旁生产可在多个中心生产出一致的CAR-T细胞产品，这些产品对B细胞恶性肿瘤患者的治疗有效。
Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5 97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.
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