Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Hematology, Yuncheng Central Hospital, Shanxi Medical University, Yuncheng, China.
Cytotherapy. 2019 Jun;21(6):659-670. doi: 10.1016/j.jcyt.2019.03.313. Epub 2019 Apr 25.
Chimeric antigen receptor (CAR)-T cell therapy opens a new era for cancer treatment. However, in prolonged follow-up, relapse has emerged as one of the major obstacles. Dendritic cell (DC) vaccination is a promising treatment to eradicate tumor cells and prevent relapse. The epidermal growth factor receptor (EGFR) pathway substrate 8 (Eps8) gene is involved in regulating cancer progression and is considered an attractive target for specific cancer immunotherapy. The purpose of this study was to explore a combinatorial therapy using CAR-T cells and a DC vaccine such as Eps8-DCs to increase leukemia treatment efficacy.
We pulsed DCs with Eps8-derived peptides to generate Eps8-DCs, engineered T cells to express a second-generation CAR specific for CD19, and analyzed the effects of the Eps8-DCs on the in vitro expansion, phenotype and effector functions of the CD19 CAR-T cells.
The Eps8-DCs significantly reduced the activation-induced cell death and enhanced the proliferative potential of CAR-T cells during in vitro expansion. In addition, the expanded T cells co-cultured with the Eps8-DCs exhibited an increased percentage of central memory T cells (Tcms) and a decreased percentage of effector memory T cells (Tems). The Eps8-DCs enhanced CD19 CAR-T cell immune functions, including cytokine production, CD107a degranulation activity and cytotoxicity.
This study demonstrates that Eps8-DCs exert synergistic effect on CD19 targeting CAR-T cells and paves the way for clinical trials using the combination of DC vaccination and engineered T cells in relapsed leukemia.
嵌合抗原受体（CAR）-T 细胞疗法为癌症治疗开辟了一个新时代。然而，在长期随访中，复发已成为主要障碍之一。树突状细胞（DC）疫苗接种是一种有前途的治疗方法，可以消灭肿瘤细胞并防止复发。表皮生长因子受体（EGFR）途径底物 8（Eps8）基因参与调节癌症进展，被认为是特异性癌症免疫治疗的一个有吸引力的靶点。本研究旨在探索使用 CAR-T 细胞和 DC 疫苗（如 Eps8-DC）的组合疗法来提高白血病的治疗效果。
我们用 Eps8 衍生肽脉冲 DC 产生 Eps8-DC，工程化 T 细胞表达针对 CD19 的第二代 CAR，并分析 Eps8-DC 对 CD19 CAR-T 细胞体外扩增、表型和效应功能的影响。
Eps8-DC 显著降低了 CAR-T 细胞体外扩增过程中的激活诱导细胞死亡，并增强了其增殖潜力。此外，与 Eps8-DC 共培养的扩增 T 细胞中中央记忆 T 细胞（Tcms）的比例增加，效应记忆 T 细胞（Tems）的比例降低。Eps8-DC 增强了 CD19 CAR-T 细胞的免疫功能，包括细胞因子产生、CD107a 脱颗粒活性和细胞毒性。
本研究表明，Eps8-DC 对 CD19 靶向 CAR-T 细胞具有协同作用，为在复发白血病中使用 DC 疫苗接种和工程化 T 细胞联合治疗的临床试验铺平了道路。
