PDF(Pubmed)
Abstract：
Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.
摘要：
尽管CART细胞疗法治疗复发性/难治性大B细胞淋巴瘤（R/RLBCL）的结果良好，仍然存在一些挑战，包括不完整的反应，免疫介导的毒性，和抗原丢失复发。我们描述了与目前批准的CAR-T细胞疗法相比的新方法的相对临床益处。在缺乏头对头比较和随机对照试验的情况下，我们进行了匹配的调整间接比较，以量化实验性CAR对Axicabtageneciloleucel（Yescarta）的相对疗效和安全性，第一个FDA批准的汽车。来自15项具有个体患者数据(IPD)的临床试验的总共182名R/RLBCL患者通过其CART细胞构建体和+/-ASCT状态汇集成8个群体。研究终点为无进展生存期(PFS)，≥3级细胞因子释放综合征（CRS），和≥3级神经毒性（NT）。串联CD19。CD20.4-1BBζCAR显示出良好的疗效和安全性，而与Yescarta相比，CD19和CD20与4-1BBζ的共输注没有临床益处。第三代CD19。CD28.4-1BBζ,和顺序施用自体干细胞移植（ASCT）和CD19。除了ASCT联合干预措施暗示NT风险高于Yescarta外，CAR在统计学上无统计学意义，但PFS和安全性得到了改善。具有修饰的共刺激结构域以降低毒性的CAR(Hu19。CD8.28Zζ和CD19。BBz.86ζ)表现出显著的安全性，没有严重的不良事件；然而，两者的PFS都比Yescarta差.第三代CAR在统计学上显着低于Yescarta。CD20。4-1BBζ数据表明，与Yescarta相比，仅靶向CD20抗原缺乏临床或安全性益处。需要与其他FDA批准的CAR进行进一步比较。
