Division of Oncology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
Cancer Discov. 2019 Apr;9(4):492-499. doi: 10.1158/2159-8290.CD-18-1314. Epub 2019 Jan 10.
Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well , but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies...
嵌合抗原受体 (CAR) T 细胞试验的转化数据表明，在生产前产品中存在幼稚 T 细胞对于临床反应和持久性很重要。为了开发针对其他肿瘤的 CAR 试验，我们研究了诊断时和每个化疗周期后患有实体瘤和淋巴瘤的儿童的 T 细胞分布。我们发现，富含幼稚和干细胞中央记忆细胞的 T 细胞扩增良好，但大多数肿瘤类型表现出与化疗相关的早期谱系细胞耗竭，相应地刺激反应成功下降。出乎意料的是，许多患有实体瘤的儿科患者在任何治疗之前都有较少的幼稚 T 细胞。这些数据表明，CAR T 细胞的制造可能需要根据每种疾病类型中可用 T 细胞的性质进行定制。意义：累积化疗周期会耗尽许多儿科癌症方案中的幼稚 T 细胞，从而降低与成功过继细胞疗法相关的扩增潜力。在诊断时也可以看到幼稚 T 细胞缺陷，这意味着在化疗之前就存在免疫缺陷，这也可能影响免疫为基础的治疗方法的发展。
