Division of Hematology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
Clin Cancer Res. 2021 Jun 1;27(11):3141-3153. doi: 10.1158/1078-0432.CCR-20-2540. Epub 2021 Feb 2.
The development of safe and effective chimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has largely been limited by the concomitant expression of most AML-associated surface antigens on normal myeloid progenitors and by the potential prolonged disruption of normal hematopoiesis by the immunotargeting of these antigens. The purpose of this study was to evaluate B7-homolog 3 (B7-H3) as a potential target for AML-directed CAR T-cell therapy. B7-H3, a coreceptor belonging to the B7 family of immune checkpoint molecules, is overexpressed on the leukemic blasts of a significant subset of patients with AML and may overcome these limitations as a potential target antigen for AML-directed CAR-T therapy.
B7-H3 expression was evaluated on AML cell lines, primary AML blasts, and normal bone marrow progenitor populations. The antileukemia efficacy of B7-H3-specific CAR-T cells (B7-H3.CAR-T) was evaluated using coculture models and xenograft models of disseminated AML, including patient-derived xenograft models. The potential hematopoietic toxicity of B7-H3.CAR-Ts was evaluated using colony formation assays and in a humanized mouse model.
B7-H3 is expressed on monocytic AML cell lines and on primary AML blasts from patients with monocytic AML, but is not significantly expressed on normal bone marrow progenitor populations. B7-H3.CAR-Ts exhibit efficient antigen-dependent cytotoxicity and in xenograft models of AML, and are unlikely to cause unacceptable hematopoietic toxicity.
B7-H3 is a promising target for AML-directed CAR-T therapy. B7-H3.CAR-Ts control AML and have a favorable safety profile in preclinical models.
安全有效的嵌合抗原受体 (CAR) T 细胞疗法治疗急性髓细胞白血病 (AML) 的发展在很大程度上受到以下因素的限制：大多数 AML 相关表面抗原同时在正常髓样祖细胞上表达，以及这些抗原的免疫靶向可能会长期破坏正常造血。本研究旨在评估 B7-同源物 3 (B7-H3) 作为 AML 定向 CAR T 细胞治疗的潜在靶点。B7-H3 是免疫检查点分子 B7 家族的一个共受体，在相当一部分 AML 患者的白血病细胞上过度表达，并且可能克服这些限制，成为 AML 定向 CAR-T 治疗的潜在靶抗原。
评估 AML 细胞系、原代 AML blasts 和正常骨髓祖细胞群体中 B7-H3 的表达。使用共培养模型和 AML 播散的异种移植模型（包括患者来源的异种移植模型）评估 B7-H3 特异性 CAR-T 细胞（B7-H3.CAR-T）的抗白血病疗效。使用集落形成测定和人源化小鼠模型评估 B7-H3.CAR-T 的潜在造血毒性。
B7-H3 在单核细胞性 AML 细胞系和单核细胞性 AML 患者的原代 AMLblasts 上表达，但在正常骨髓祖细胞群体上表达不明显。B7-H3.CAR-T 表现出高效的抗原依赖性细胞毒性，并在 AML 的异种移植模型中发挥作用，不太可能引起不可接受的造血毒性。
B7-H3 是 AML 定向 CAR-T 治疗的一个有前途的靶点。B7-H3.CAR-T 控制 AML，并在临床前模型中具有良好的安全性。
