PDF(Pubmed)
Abstract：
Acute myeloid leukemia (AML), a fast-progressing hematological malignancy affecting myeloid cells, is typically treated with chemotherapy or hematopoietic stem cell transplantation. However, approximately half of the patients face relapses and 5-year survival rates are poor. With the goal to facilitate dual-specificity, boosting anti-tumor activity, and minimizing the risk for antigen escape, this study focused on combining chimeric antigen receptor (CAR) and T cell receptor (TCR) technologies. CAR\'TCR-T cells, co-expressing a CD33-CAR and a transgenic dNPM1-TCR, revealed increased and prolonged anti-tumor activity in vitro, particularly in case of low target antigen expression. The distinct transcriptomic profile suggested enhanced formation of immunological synapses, activation, and signaling. Complete elimination of AML xenografts in vivo was only achieved with a cell product containing CAR\'TCR-T, CAR-T, and TCR-T cells, representing the outcome of co-transduction with two lentiviral vectors encoding either CAR or TCR. A mixture of CAR-T and TCR-T cells, without CAR\'TCR-T cells, did not prevent progressive tumor outgrowth and was comparable to treatment with CAR-T and TCR-T cells individually. Overall, our data underscore the efficacy of co-expressing CAR and transgenic TCR in one T cell, and might open a novel therapeutic avenue not only for AML but also other malignancies.
摘要：
急性髓系白血病(AML),影响骨髓细胞的快速发展的血液恶性肿瘤，通常用化疗或造血干细胞移植治疗。然而,大约一半的患者面临复发,5年生存率很低.以促进双重特异性为目标，增强抗肿瘤活性，并将抗原逃逸的风险降至最低，这项研究的重点是结合嵌合抗原受体（CAR）和T细胞受体（TCR）技术。CAR\'TCR-T细胞，共表达CD33-CAR和转基因dNPM1-TCR，显示体外抗肿瘤活性增加和延长，特别是在低靶抗原表达的情况下。不同的转录组特征表明免疫突触的形成增强，激活,和信号。AML异种移植物在体内的完全消除只能用含有CAR/TCR-T的细胞产物实现，CAR-T,和TCR-T细胞，表示与编码CAR或TCR的两种慢病毒载体共转导的结果。CAR-T和TCR-T细胞的混合物，没有CAR\'TCR-T细胞，没有阻止进行性肿瘤生长，与分别用CAR-T和TCR-T细胞治疗相当。总的来说,我们的数据强调了在一个T细胞中共表达CAR和转基因TCR的功效，并可能为AML和其他恶性肿瘤开辟一条新的治疗途径。
