Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.
Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.
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肿瘤微环境对大B细胞淋巴瘤抗CD19 CAR T细胞疗法或化疗和移植疗效的影响。
DOI：
10.1038/s41591-023-02754-1
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发表时间：
2024
期刊：
影响因子：
82.9
通讯作者：
Budka,
中科院分区：
文献类型：
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作者：
Locke,FrederickL;Filosto,Simone;Chou,Justin;Vardhanabhuti,Saran;Perbost,Regis;Dreger,Peter;Hill,BrianT;Lee,Catherine;Zinzani,PierL;Kröger,Nicolaus;López-Guillermo,Armando;Greinix,Hildegard;Zhang,Wangshu;Tiwari,Gayatri;Budka,
二线大B细胞淋巴瘤的3期ZUMA-7试验表明，抗cd19 CAR - T细胞疗法（axicabtagene ciloleucel（轴细胞））优于标准护理（SOC；补救性化疗后造血移植）（NCT03391466）。在这里，我们提出了一项预先指定的探索性分析，研究了预处理肿瘤特征与轴细胞抗SOC疗效之间的关系。B细胞基因表达特征（GES）和CD19表达与轴细胞无事件生存率显著相关（B细胞GES P= 0.0002， CD19表达P= 0.0165），但与SOC无关（B细胞GES P= 0.9374， CD19表达P= 0.5526）。无论B细胞GES和CD19表达水平如何，axis -cel均表现出优于SOC的无事件生存（B细胞GES高P= 8.56 × 10 - 9， B细胞GES低P= 0.0019， CD19基因高P= 3.85 × 10 - 9， CD19基因低P= 0.0017）。恶性细胞中CD19的低表达与由免疫抑制基质和髓系基因组成的肿瘤GES相关，突出了恶性细胞特征与免疫环境之间的相互关系，极大地影响了轴细胞的预后。肿瘤负荷、乳酸脱氢酶和细胞来源对SOC的影响大于轴细胞结果。与轴细胞预后改善相关的T细胞活化和B细胞GES随着治疗线的增加而降低。这些数据强调了对轴细胞和SOC的抗性机制的差异，并支持轴细胞的早期干预。
The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) (NCT03391466). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P= 0.0002 for B cell GES;P= 0.0165 for CD19 expression) but not SOC (P= 0.9374 for B cell GES;P= 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P= 8.56 × 10–9for B cell GES high;P= 0.0019 for B cell GES low;P= 3.85 × 10–9for CD19 gene high;P= 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.