肿瘤细胞治疗研究
英文原题：Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia.
Radiation therapy improves CAR T cell activity in acute lymphoblastic leukemia.
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自体 T 细胞经工程化表达针对 CD19 的嵌合抗原受体（CAR）已获批用于治疗多种 CD19+血液系统恶性肿瘤。
自体T细胞经工程化改造以表达针对CD19的嵌合抗原受体（CAR）已被批准用于治疗多种CD19+血液系统恶性肿瘤。尽管CAR-T 细胞可在多数患者中诱导客观缓解，但肿瘤细胞丢失CD19表达后常发生复发。在胰腺癌临床前模型中，放射治疗（RT）已成功用于规避CAR靶点丢失。这至少部分反映了RT能够诱导恶性细胞表达死亡受体（DR），从而至少实现一定程度的非CAR依赖性肿瘤杀伤。在CD19+急性淋巴细胞白血病（ALL）的人源模型中，我们在体外和体内也观察到RT可上调DR。此外，在CAR-T 细胞输注前对荷ALL小鼠进行低剂量全身照射（LD-TBI），可显著延长单独CAR-T 细胞所带来的总生存期获益。这种治疗活性的改善伴随着CAR-T 细胞在体内更优的扩增。这些数据鼓励在血液系统恶性肿瘤患者中启动将LD-TBI与CAR-T 细胞联合的临床试验。
Autologous T cells engineered to express a chimeric antigen receptor (CAR) specific for CD19 are approved for the treatment of various CD19 + hematological malignancies. While CAR T cells induce objective responses in a majority of patients, relapse frequently occurs upon loss of CD19 expression by neoplastic cells. Radiation therapy (RT) has been successfully employed to circumvent the loss of CAR targets in preclinical models of pancreatic cancer. At least in part, this reflects the ability of RT to elicit death receptor (DR) expression by malignant cells, enabling at least some degree of CAR-independent tumor killing. In a human model of CD19 + acute lymphoblastic leukemia (ALL), we also observed DR upregulation by RT, both in vitro and in vivo. Moreover, low-dose total body irradiation (LD-TBI) delivered to ALL-bearing mice prior to CAR T cell infusion considerably extended the overall survival benefit afforded by CAR T cells alone. Such an improved therapeutic activity was accompanied by a superior expansion of CAR T cells in vivo. These data encourage the initiation of clinical trials combining LD-TBI with CAR T cells in patients with hematological malignancies.
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