Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX 77030, USA.
Leukemia. 2013 Jul;27(7):1538-47. doi: 10.1038/leu.2013.66. Epub 2013 Mar 1.
Adoptive immunotherapy with ex vivo expanded T cells is a promising approach to prevent or treat leukemia. Myeloid leukemias express tumor-associated antigens (TAA) that induce antigen-specific cytotoxic T lymphocyte (CTL) responses in healthy individuals. We explored the feasibility of generating TAA-specific CTLs from stem cell donors of patients with myeloid leukemia to enhance the graft-versus-leukemia effect after stem cell transplantation. CTL lines were manufactured from peripheral blood of 10 healthy donors by stimulation with 15mer peptide libraries of five TAA (proteinase 3 (Pr3), preferentially expressed antigen in melanoma, Wilms tumor gene 1 (WT1), human neutrophil elastase (NE) and melanoma-associated antigen A3) known to be expressed in myeloid leukemias. All CTL lines responded to the mix of five TAA and were multi-specific as assessed by interferon-γ enzyme-linked immunospot. Although donors showed individual patterns of antigen recognition, all responded comparably to the TAAmix. Immunogenic peptides of WT1, Pr3 or NE could be identified by epitope mapping in all donor CTL lines. In vitro experiments showed recognition of partially human leukocyte antigen (HLA)-matched myeloid leukemia blasts. These findings support the development of a single clinical grade multi-tumor antigen-specific T-cell product from the stem cell source, capable of broad reactivity against myeloid malignancies for use in donor-recipient pairs without limitation to a certain HLA-type.
过继性免疫疗法使用体外扩增的 T 细胞是预防或治疗白血病的一种有前途的方法。髓系白血病表达肿瘤相关抗原 (TAA)，这些抗原在健康个体中诱导抗原特异性细胞毒性 T 淋巴细胞 (CTL) 反应。我们探索了从髓系白血病患者的干细胞供体中产生 TAA 特异性 CTL 的可行性，以增强干细胞移植后的移植物抗白血病效应。CTL 系是通过用已知在髓系白血病中表达的五种 TAA（蛋白酶 3 (Pr3)、黑色素瘤优先表达抗原、Wilms 瘤基因 1 (WT1)、人中性粒细胞弹性蛋白酶 (NE) 和黑色素瘤相关抗原 A3）的 15 mer 肽文库刺激 10 名健康供体的外周血产生的。所有 CTL 系均对 TAAmix 产生反应，通过干扰素-γ酶联免疫斑点法评估为多特异性。尽管供体表现出个体的抗原识别模式，但所有供体 CTL 系对 TAAmix 的反应相当。通过表位作图在所有供体 CTL 系中均可鉴定出 WT1、Pr3 或 NE 的免疫原性肽。体外实验显示对部分人白细胞抗原 (HLA) 匹配的髓系白血病母细胞的识别。这些发现支持从干细胞来源开发单一临床级多肿瘤抗原特异性 T 细胞产品，该产品能够广泛针对髓系恶性肿瘤反应，用于供受者对，不受特定 HLA 型的限制。
