Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T.

Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status.

We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration.

TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

肿瘤固有特征可能使大 B 细胞淋巴瘤 (LBCL) 对 CD19 定向嵌合抗原受体 T 细胞 (CAR-T) 不敏感。我们假设 TP53 基因组改变不利于用 CD19-CAR-T 治疗的 LBCL 的反应结果。

包括接受 CD19-CAR-T 治疗的 LBCL 患者。对一部分患者的 pre-CAR-T 肿瘤样本进行了靶向下一代测序。通过组织学、细胞遗传学和分子特征评估反应率和存活率。在具有基因组和转录组学分析的新诊断 LBCL 队列中，我们研究了细胞通路与TP53状态之间的相互作用。

我们纳入了 153 名接受 CD19-CAR-T（axicabtagene ciloleucel [50%]、tisagenlecleucel [32%] 和 lisocabtagene maraleucel [18%]）治疗的复发或难治性 LBCL 成人。结果与关键试验相呼应：完全缓解 (CR) 率为 54%，中位总生存期 (OS) 为 21.1 个月（95% CI，14.8 至未达到），无进展生存期为 6 个月（3.4 至 9.7）。组织学和细胞遗传学 LBCL 特征不能预测 CR。在具有下一代测序分析的 82 名患者的子集中，CR 和 OS 率与未测序队列相当。TP53改变（突变和/或拷贝数改变）很常见 (37%)，并且与单变量和多变量回归模型中较差的 CR 和 OS 率相关；TP53中的 1 年 OS-改变的 LBCL 为 44%（95% CI，29 至 67），而野生型为 76%（65 至 89）（P = .012）。来自另一组新诊断淋巴瘤患者 (n = 562) 的转录组学分析表明，TP53改变与 CAR-T 细胞毒性相关通路失调有关，包括干扰素和死亡受体信号通路以及 CD8 T 细胞肿瘤减少浸润。

TP53是一种有效的肿瘤内在生物标志物，可以为接受 CD19-CAR-T 治疗的 LBCL 患者的风险分层和临床试验设计提供信息。TP53 的作用应在独立队列中进一步验证。