CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant.

IF 23.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2025-03-24 DOI:10.1038/s43018-025-00934-1

Shunya Ikeda, Kana Hasegawa, Yosuke Kogue, Takao Arimori, Ryuhei Kawamoto, Tansri Wibowo, Moto Yaga, Yuri Inada, Hirofumi Uehara, Miwa Matsubara, Mana Tachikawa, Makiko Suga, Shuhei Kida, Kumi Shibata, Kazuhito Tsutsumi, Kentaro Fukushima, Jiro Fujita, Tomoaki Ueda, Shinsuke Kusakabe, Akihisa Hino, Michiko Ichii, Asao Hirose, Hirohisa Nakamae, Masayuki Hino, Takafumi Nakao, Megumu Inoue, Kyoko Yoshihara, Satoshi Yoshihara, Shuji Ueda, Tetsuro Tachi, Hideki Kuroda, Koki Murakami, Noriyuki Kijima, Haruhiko Kishima, Eri Igashira, Mari Murakami, Tsuyoshi Takiuchi, Tadashi Kimura, Takashi Hiroshima, Toru Kimura, Yasushi Shintani, Chihaya Imai, Kosuke Yusa, Ryota Mori, Takayuki Ogino, Hidetoshi Eguchi, Kiyoshi Takeda, Yusuke Oji, Atsushi Kumanogoh, Junichi Takagi, Naoki Hosen

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引用次数: 0

Abstract

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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针对异体造血干细胞移植后急性髓性白血病中不匹配的 HLA-DR 分子的 CAR T 细胞或 NK 细胞。

急性髓性白血病（AML）特异性靶抗原很难确定。在这里，我们证明了HLA-DRB1可作为嵌合抗原受体（CAR）T细胞的白血病特异性靶点，用于异基因造血干细胞移植（allo-HCT）后的急性髓性白血病患者。我们发现KG2032是一种单克隆抗体，能与约半数患者的AML细胞特异性结合，但不能与B淋巴细胞以外的正常白细胞特异性结合。KG2032与HLA-DRB1分子的一个子集发生反应，特别是那些第86个氨基酸不是天冬氨酸的分子。KG2032 与非造血组织的反应极少。这些结果表明，对于携带KG2032反应性HLA-DRB1等位基因并接受了来自携带KG2032非反应性HLA-DRB1等位基因供体的异体HCT的患者，KG2032反应性对AML细胞具有高度特异性。在雌性小鼠的临床前模型中，KG2032衍生的CAR T细胞或自然杀伤细胞显示出显著的抗白血病活性，这表明它们可以治愈接受同种异体HCT仍无法治愈的急性髓细胞白血病患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.