肿瘤细胞治疗研究
英文原题：CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.
CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.
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这些结果表明，对于携带 KG2032 反应性 HLA-DRB1 等位基因、且接受了来自携带 KG2032 非反应性 HLA-DRB1 等位基因供者的 allo-HCT 的患者，KG2032 反应性对 AML 细胞具有高度特异性。
急性髓系白血病（AML）特异性靶抗原难以识别。本研究显示，异基因造血干细胞移植（allo-HCT）后，HLA-DRB1 可作为 AML 患者嵌合抗原受体（CAR）T 细胞的白血病特异性靶点。研究者发现单克隆抗体 KG2032 可特异性结合约半数患者的 AML 细胞，但不会结合 B 淋巴细胞以外的正常白细胞。KG2032 可识别一部分 HLA-DRB1 分子，特征为第 86 位氨基酸不是天冬氨酸。KG2032 与非造血组织的反应极低。这些结果表明，对于携带 KG2032 反应性 HLA-DRB1 等位基因、且接受携带 KG2032 非反应性 HLA-DRB1 等位基因供者 allo-HCT 的患者，KG2032 反应性对其 AML 细胞具有高度特异性。由 KG2032 衍生的 CAR-T 或NK 细胞在雌性小鼠临床前模型中显示显著抗白血病活性，提示此类疗法可能治愈 allo-HCT 仍无法治愈的 AML 患者。
Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRB1 can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRB1 alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.
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