Harrop Richard, Blount Daniel G, Khan Naeem, Soyombo Mayowa, Moyce Laura, Drayson Mark T, Down Jenny, Lawson Michelle A, O'Connor Deirdre, Nimmo Rachael, Lad Yatish, Souberbielle Bernard, Mitrophanous Kyriacos, Ettorre Anna
Oxford Biomedica (UK) Limited, Oxford, United Kingdom.
Clinical Immunology Service, University of Birmingham, Birmingham, United Kingdom.
Mol Cancer Ther. 2025 Jan 2;24(1):93-104. doi: 10.1158/1535-7163.MCT-24-0052.
Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome deficits in the ability of the host immune system to detect and subsequently eradicate tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step for a targeted therapy that selectively targets cancer cells without affecting normal tissues. 5T4 is a tumor-associated antigen expressed on the cell surface of most solid tumors. However, very little is known about its expression in hematologic malignancies. In this study, we assess the expression of 5T4 in different types of leukemias, specifically acute myeloid leukemia (AML), and normal hematopoietic stem cells (HSC). We also provide an in vitro assessment of safety and efficacy of 5T4-targeting CAR T cells against HSCs and AML tumor cell lines. 5T4 expression was seen in about 50% of AML cases; AML with mutated nucleophosmin 1, AML-myelodysplasia-related, and AML not otherwise specified showed the highest percentage of 5T4+ cases. 5T4 CAR T cells efficiently and specifically killed AML tumor cell lines, including leukemic stem cells. Coculture of 5T4 CAR T cells with HSCs from healthy donors showed no impact on subsequent colony formation, thus confirming the safety profile of 5T4. A proof-of-concept study using a murine model for AML demonstrated that CAR T cells recognize 5T4 expressed on cells and can kill tumor cells both in vitro and in vivo. These results highlight 5T4 as a promising target for immune intervention in AML and that CAR T cells can be considered a powerful personalized therapeutic approach to treat AML.
嵌合抗原受体（CAR）T细胞代表了一种新型的靶向方法，以克服宿主免疫系统检测并随后根除肿瘤能力的缺陷。鉴定肿瘤细胞表面特异性表达的抗原是靶向治疗的关键第一步，该靶向治疗可选择性地靶向癌细胞而不影响正常组织。5T4是一种在大多数实体瘤细胞表面表达的肿瘤相关抗原。然而，关于其在血液系统恶性肿瘤中的表达知之甚少。在本研究中，我们评估了5T4在不同类型白血病，特别是急性髓系白血病（AML）以及正常造血干细胞（HSC）中的表达。我们还提供了针对HSC和AML肿瘤细胞系的5T4靶向CAR T细胞安全性和有效性的体外评估。在约50%的AML病例中可见5T4表达；核磷蛋白1突变的AML、与骨髓增生异常相关的AML以及未另行指定的AML显示5T4阳性病例的比例最高。5T4 CAR T细胞有效且特异性地杀死AML肿瘤细胞系，包括白血病干细胞。5T4 CAR T细胞与健康供体的HSC共培养对随后的集落形成没有影响，从而证实了5T4的安全性。一项使用AML小鼠模型的概念验证研究表明，CAR T细胞可识别细胞上表达的5T4，并能在体外和体内杀死肿瘤细胞。这些结果突出了5T4作为AML免疫干预的一个有前景的靶点，并且CAR T细胞可被认为是治疗AML的一种强大的个性化治疗方法。
