Department of Hematology, Dongyang Hospital Affiliated to Wenzhou Medical University, Dongyang People's Hospital, Dongyang, Zhejiang, China.
Department of Hematology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Front Immunol. 2023 Feb 10;14:1093750. doi: 10.3389/fimmu.2023.1093750. eCollection 2023.
Chimeric antigen receptor (CAR)-T cell therapy has achieved unprecedented success in treating hematopoietic malignancies. However, this cell therapy is hampered in treating acute myeloid leukemia (AML) due to lack of ideal cell surface targets that only express on AML blasts and leukemia stem cells (LSCs) but not on normal hematopoietic stem cells (HSCs).
We detected the CD70 expression on the surfaces of AML cell lines, primary AML cells, HSC, and peripheral blood cells and generated a second-generation CD70-specific CAR-T cells using a construct containing a humanized 41D12-based scFv and a 41BB-CD3ζ intracellular signaling domain. Cytotoxicity, cytokine release, and proliferation in antigen stimulation, CD107a assay, and CFSE assays were used to demonstrate the potent anti-leukemia activity in vitro. A Molm-13 xenograft mouse model was established to evaluate the anti-leukemic activity of CD70 CAR-T . CFU assay was explored to assess the safety of CD70 CAR-T on HSC.
CD70 heterogeneously expressed on AML primary cells, including leukemia blasts, leukemic progenitor, and stem cells, but not expressed on normal HSCs and majority of blood cells. Anti-CD70 CAR-T cells exhibited potent cytotoxicity, cytokines production, and proliferation when incubated with CD70 AML cell lines. It also displayed robust anti-leukemia activity and prolonged survival in Molm-13 xenograft mouse model. However, such CAR-T cell therapy did not completely eliminate leukemia .
Our study reveals that anti-CD70 CAR-T cells are a new potential treatment for AML. However, such CAR-T cell therapy did not completely eliminate leukemia , suggesting that future studies aiming to generate innovative combinatorial CAR constructs or to increase CD70 expression density on leukemia cell surface to prolong the life-span of CAR-T cells in the circulation will be needed in order to optimize CAR-T cell responses for AML.
嵌合抗原受体 (CAR)-T 细胞疗法在治疗血液恶性肿瘤方面取得了前所未有的成功。然而，由于缺乏仅在 AML blasts 和白血病干细胞 (LSCs) 上表达而不在正常造血干细胞 (HSCs) 上表达的理想细胞表面靶点，这种细胞疗法在治疗急性髓系白血病 (AML) 方面受到限制。
我们检测了 AML 细胞系、原代 AML 细胞、HSC 和外周血细胞表面的 CD70 表达，并使用包含基于人源化 41D12 的 scFv 和 41BB-CD3ζ 细胞内信号域的构建体生成第二代 CD70 特异性 CAR-T 细胞。在抗原刺激、CD107a 测定和 CFSE 测定中，使用细胞毒性、细胞因子释放和增殖来证明体外强大的抗白血病活性。建立 Molm-13 异种移植小鼠模型以评估 CD70 CAR-T 的抗白血病活性。CFU 测定用于评估 CD70 CAR-T 在 HSC 上的安全性。
CD70 在 AML 原代细胞上呈异质性表达，包括白血病blasts、白血病祖细胞和干细胞，但不在正常 HSCs 和大多数血细胞上表达。抗-CD70 CAR-T 细胞与 CD70 AML 细胞系孵育时表现出强大的细胞毒性、细胞因子产生和增殖。它在 Molm-13 异种移植小鼠模型中也表现出强大的抗白血病活性和延长的生存时间。然而，这种 CAR-T 细胞疗法并未完全消除白血病。
我们的研究表明，抗-CD70 CAR-T 细胞是 AML 的一种新的潜在治疗方法。然而，这种 CAR-T 细胞疗法并未完全消除白血病，这表明未来需要进行旨在生成创新组合 CAR 构建体或增加白血病细胞表面 CD70 表达密度以延长 CAR-T 细胞在循环中的寿命的研究，以优化 CAR-T 细胞对 AML 的反应。
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