[CAR T 细胞疗法治疗髓系恶性肿瘤的现状与前景]。

Shoji Saito
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摘要

嵌合抗原受体(CAR)-T 细胞疗法是治疗血液恶性肿瘤最有前景的免疫疗法之一,可用于治疗髓系恶性肿瘤。然而,由于白血病细胞和患者靶抗原表达的异质性、难以排除靶上/靶下肿瘤效应以及免疫抑制性肿瘤微环境,开发治疗此类疾病的CAR-T疗法尤其具有挑战性。迄今为止,CAR-T 细胞的各种靶点(包括 CD33、NKG2D、CD123、CLL-1 和 CD7)已得到积极研究,尤其是针对急性髓性白血病(AML)。虽然目前还没有 CAR-T 细胞产品获得批准,但一些临床试验已显示出良好的效果,尤其是针对 CLL-1 和 CD123 的临床试验。此外,新的理想靶点和异体或现成 CAR-T 细胞产品的使用也在研究之中。同时,CAR-T疗法对其他骨髓恶性肿瘤(包括骨髓增生异常综合征和骨髓增生性疾病)是否有效仍是未知数。本综述从靶抗原特性和疾病特异性靶上/靶下毒性的角度,讨论了针对髓系恶性肿瘤,尤其是急性髓细胞白血病的 CAR-T 疗法开发所面临的挑战。此外,它还讨论了治疗这些疾病的 CAR-T 细胞的临床开发和前景。
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[Current state and future prospects of CAR T-cell therapy for myeloid malignancies].

Chimeric antigen receptor (CAR)-T cell therapy is among the most promising immunotherapies for hematological malignancies and can be used to treat myeloid malignancies in practice. However, developing CAR-T therapies for such diseases is particularly challenging due to the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-target/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells, especially for acute myeloid leukemia (AML). Although no CAR-T cell products have been approved, several clinical trials have shown promising results, particularly for those targeting CLL-1 and CD123. Furthermore, new ideal targets and use of allogeneic or off-the-shelf CAR-T cell products are under investigation. Meanwhile, it remains unknown whether CAR-T therapy would be effective for other myeloid malignancies, including myelodysplastic syndromes and myeloproliferative diseases. This review discusses challenges in the development of CAR-T therapy for myeloid malignancies, especially for AML, from the perspectives of target antigen characteristics and disease-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of CAR-T cells for these diseases.

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