肿瘤细胞治疗研究
英文原题：T cells engineered against Dickkopf-1-A2 complex can be used to treat HLA-A2(+) solid and hematologic cancers.
本研究表明 DKK1-A2 CAR-T 细胞或可用于治疗人类癌症。
尽管嵌合抗原受体（CAR）T细胞有望治疗血液系统肿瘤，但开发有效的实体瘤CAR-T仍具挑战。Dickkopf-1（DKK1）蛋白在人类血液系统和实体肿瘤中广泛表达。研究者采用识别DKK1-A2复合物（HLA-A*0201呈递的DKK1-P20肽）的鼠源或人源化单克隆抗体序列，制备DKK1-A2 CAR-T。该复合物在所有检测的HLA-A2阳性肿瘤样本中均可检测到，在正常组织中则未检出（扁桃体除外）。DKK1-A2 CAR-T可特异且有效地裂解HLA-A2阳性、DKK1表达肿瘤细胞，但不杀伤HLA-A2阳性健康供者的血液或骨髓细胞。在人骨髓瘤、胰腺癌、肺癌和乳腺癌异种移植模型，以及胰腺癌患者来源异种移植模型中，DKK1-A2 CAR-T（而非CD19 CAR-T）均可有效控制或清除已建立肿瘤；在NSG小鼠或人DKK1及HLA-A2转基因小鼠中均未检测到毒性。本研究提示DKK1-A2 CAR-T可能用于治疗人类癌症。
Although chimeric antigen receptor (CAR)-T cells are promising effector cells to treat hematologic tumors, developing effective CAR-T cells for solid tumors remains challenging. Dickkopf-1 (DKK1) protein is widely expressed by human hematologic and solid tumors. Using the sequence of murine or humanized monoclonal antibody recognizing DKK1-A2 complexes (DKK1-P20 peptide in the context of HLA-A*0201) that are detected on all examined HLA-A2 + tumor samples but not normal tissues except tonsils, we generate DKK1-A2 CAR-T cells that specifically and effectively lyse HLA-A2- and DKK1-expressing tumor cells but not blood or bone marrow cells from HLA-A2 + healthy donors. In xenograft models of human myeloma, pancreatic, lung, and breast cancers and patient-derived xenograft of pancreatic cancer, DKK1-A2 but not CD19 CAR-T cells effectively control or eradicate established tumors without detectable toxicities in NSG or human DKK1 and HLA-A2-trangenic mice. This study indicates that DKK1-A2 CAR-T cells may be used to treat human cancers.
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