Hasegawa Aiko, Saito Shoji, Narimatsu Shogo, Nakano Shigeru, Nagai Mika, Ohnota Hideki, Inada Yoichi, Morokawa Hirokazu, Nakashima Ikumi, Morita Daisuke, Ide Yuichiro, Matsuda Kazuyuki, Tashiro Haruko, Yagyu Shigeki, Tanaka Miyuki, Nakazawa Yozo
Department of Pediatrics Shinshu University School of Medicine Matsumoto Japan.
Center for Advanced Research of Gene and Cell Therapy Shinshu University Matsumoto Japan.
Clin Transl Immunology. 2021 May 6;10(5):e1282. doi: 10.1002/cti2.1282. eCollection 2021.
As the prognosis of relapsed/refractory (R/R) acute myeloid leukaemia (AML) remains poor, novel treatment strategies are urgently needed. Clinical trials have shown that chimeric antigen receptor (CAR)-T cells for AML are more challenging than those targeting CD19 in B-cell malignancies. We recently developed -modified ligand-based CAR-T cells that target CD116/CD131 complexes, also known as the GM-CSF receptor (GMR), for the treatment of juvenile myelomonocytic leukaemia. This study therefore aimed to develop a novel therapeutic method for R/R AML using GMR CAR-T cells.
To further improve the efficacy of the original GMR CAR-T cells, we have developed novel GMR CAR vectors incorporating a mutated GM-CSF for the antigen-binding domain and G4S spacer. All GMR CAR-T cells were generated using a -based gene transfer system. The anti-tumor effect of GMR CAR-T cells was tested in mouse AML xenograft models.
Nearly 80% of the AML cells predominant in myelomonocytic leukaemia were found to express CD116. GMR CAR-T cells exhibited potent cytotoxic activities against CD116 AML cells . Furthermore, GMR CAR-T cells incorporating a G4S spacer significantly improved long-term and anti-tumor effects. By employing a mutated GM-CSF at residue 21 (E21K), the anti-tumor effects of GMR CAR-T cells were also improved especially in long-term settings. Although GMR CAR-T cells exerted cytotoxic effects on normal monocytes, their lethality on normal neutrophils, T cells, B cells and NK cells was minimal.
GMR CAR-T cell therapy represents a promising strategy for CD116 R/R AML.
由于复发/难治性（R/R）急性髓系白血病（AML）的预后仍然很差，迫切需要新的治疗策略。临床试验表明，用于AML的嵌合抗原受体（CAR）-T细胞比靶向B细胞恶性肿瘤中CD19的CAR-T细胞更具挑战性。我们最近开发了基于修饰配体的CAR-T细胞，其靶向CD116/CD131复合物，也称为GM-CSF受体（GMR），用于治疗青少年髓单核细胞白血病。因此，本研究旨在开发一种使用GMR CAR-T细胞治疗R/R AML的新方法。
为了进一步提高原始GMR CAR-T细胞的疗效，我们开发了新型GMR CAR载体，其在抗原结合域和G4S间隔区中包含突变的GM-CSF。所有GMR CAR-T细胞均使用基于[具体基因转移系统名称未给出]的基因转移系统产生。在小鼠AML异种移植模型中测试了GMR CAR-T细胞的抗肿瘤作用。
发现髓单核细胞白血病中占主导地位的近80%的AML细胞表达CD116。GMR CAR-T细胞对CD116 AML细胞表现出强大的细胞毒活性。此外，包含G4S间隔区的GMR CAR-T细胞显著改善了长期的抗肿瘤作用。通过在第21位残基处使用突变的GM-CSF（E21K），GMR CAR-T细胞的抗肿瘤作用也得到了改善，特别是在长期情况下。尽管GMR CAR-T细胞对正常单核细胞有细胞毒作用，但其对正常中性粒细胞、T细胞、B细胞和NK细胞的致死性最小。
GMR CAR-T细胞疗法是治疗CD116 R/R AML的一种有前景的策略。
