Center for Cellular Engineering, Department of Transfusion Medicine and Cellular Engineering, NIH Clinical Center, Bethesda, MD, USA.
Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD, USA.
Sci Rep. 2022 Feb 18;12(1):2830. doi: 10.1038/s41598-022-06830-3.
CD19 CAR T-cell immunotherapy is a breakthrough treatment for B cell malignancies, but relapse and lack of response remain a challenge. The bone marrow microenvironment is a key factor in therapy resistance, however, little research has been reported concerning the relationship between transcriptomic profile of bone marrow prior to lymphodepleting preconditioning and clinical response following CD19 CAR T-cell therapy. Here, we applied comprehensive bioinformatic methods (PCA, GO, GSEA, GSVA, PAM-tools) to identify clinical CD19 CAR T-cell remission-related genomic signatures. In patients achieving a complete response (CR) transcriptomic profiles of bone marrow prior to lymphodepletion showed genes mainly involved in T cell activation. The bone marrow of CR patients also showed a higher activity in early T cell function, chemokine, and interleukin signaling pathways. However, non-responding patients showed higher activity in cell cycle checkpoint pathways. In addition, a 14-gene signature was identified as a remission-marker. Our study indicated the indexes of the bone marrow microenvironment have a close relationship with clinical remission. Enhancing T cell activation pathways (chemokine, interleukin, etc.) in the bone marrow before CAR T-cell infusion may create a pro-inflammatory environment which improves the efficacy of CAR T-cell therapy.
嵌合抗原受体 T 细胞免疫疗法是治疗 B 细胞恶性肿瘤的突破性疗法，但复发和无反应仍然是一个挑战。骨髓微环境是治疗耐药的一个关键因素，但关于淋巴耗竭预处理前骨髓转录组谱与 CD19 CAR T 细胞治疗后的临床反应之间的关系，研究甚少。在这里，我们应用综合生物信息学方法（PCA、GO、GSEA、GSVA、PAM-tools）来鉴定与临床 CD19 CAR T 细胞缓解相关的基因组特征。在达到完全缓解（CR）的患者中，淋巴耗竭前骨髓的转录组谱显示主要涉及 T 细胞激活的基因。CR 患者的骨髓还显示出早期 T 细胞功能、趋化因子和白细胞介素信号通路更高的活性。然而，无反应的患者表现出细胞周期检查点途径更高的活性。此外，确定了一个由 14 个基因组成的特征作为缓解标志物。我们的研究表明，骨髓微环境的指标与临床缓解密切相关。在 CAR T 细胞输注前增强骨髓中的 T 细胞激活途径（趋化因子、白细胞介素等）可能会产生一个促炎环境，从而提高 CAR T 细胞治疗的疗效。
