肿瘤细胞治疗研究
英文原题：Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.
我们的研究结果表明，AZA 可增强 AML 细胞的免疫原性，从而提高高效 CTLA-4 阴性 anti-CD123 CAR T 细胞对恶性细胞的识别和清除能力。
成功使用嵌合抗原受体（CAR）T细胞治疗急性髓系白血病（AML）受到对正常造血祖细胞的毒性和CAR T细胞持久性低的阻碍。在此，我们开发了第三代抗CD123 CAR T细胞，其具有基于人源化CSL362的ScFv和CD28-OX40-CD3细胞内信号结构域。该CAR在异种移植模型中表现出抗AML活性，而不影响健康造血系统，也不引起上皮组织损伤。白血病细胞上的CD123表达在5'-阿扎胞苷（AZA）处理后增加。对荷白血病小鼠进行AZA处理导致输注后CTLA-4阴性抗CD123 CAR T细胞数量增加。在功能上，CTLA-4阴性抗CD123 CAR T细胞对AML细胞表现出优越的细胞毒性，伴随更高的TNF产生和关键T细胞活化分子下游磷酸化的增强。我们的发现表明，AZA增加AML细胞的免疫原性，增强高效CTLA-4阴性抗CD123 CAR T细胞对恶性细胞的识别和清除。
Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3 intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4 negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4 negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNF production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 negative anti-CD123 CAR T cells.
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