Dunussi-Joannopoulos K, Dranoff G, Weinstein H J, Ferrara J L, Bierer B E, Croop J M
Dana-Farber Cancer Institute and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Blood. 1998 Jan 1;91(1):222-30.
In an attempt to explore novel treatment modalities in acute myeloid leukemia (AML), we studied the role of costimulatory and cytokine gene immunotherapy in murine AML. We have previously shown that leukemic mice can be cured with CD80 transfected leukemic cells (B7. 1-AML vaccine) administered early in the course of the disease and that the failure B7.1-AML vaccines administered late cannot be attributed to immunosuppression induced by tumor growth. CD8+ T cells, which are necessary for tumor rejection, are activated rather than suppressed during the first half of the leukemic course in nonvaccinated mice. In this report, we question whether CD86 (B7.2) or the cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), or tumor necrosis factor-alpha (TNF-alpha) can improve the vaccination potential of AML cells. The choice of cytokines was based on their combined and alone as well ability to direct the differentiation of CD34+ cells into potent antigen-presenting dendritic cells in vitro. Our studies show that (1) mice vaccinated with a leukemogenic number of AML cells engineered to express B7.2 (B7.2-AML) or to secrete GM-CSF, IL-4, or TNF-alpha (GM-, IL-4-, TNF-alpha-AML) do not develop leukemia; (2) GM-AML cells are tumorigenic in sublethally irradiated SJL/J mice but not in Swiss nu/nu mice, indicating that killing of tumor cells is not T-cell-dependent; (3) vaccines with irradiated GM-AML, but not B7.2-, IL-4-, or TNF-alpha-AML cells, can elicit leukemia-specific protective and therapeutic immunity; and (4) in head-to-head comparison experiments, vaccination with irradiated GM-AML is more potent than B7.1-AML, curing 80% and providing 20% prolonged survival of the leukemic mice at week 2, as opposed to cures only up to 1 week with B7.1-AML vaccines. These preclinical data emphasize that GM-CSF gene immunotherapy deserves clinical evaluation in AML.
为了探索急性髓系白血病（AML）的新型治疗方法，我们研究了共刺激和细胞因子基因免疫疗法在小鼠AML中的作用。我们之前已经表明，白血病小鼠在疾病早期给予转染了CD80的白血病细胞（B7.1-AML疫苗）可以治愈，而晚期给予失败的B7.1-AML疫苗不能归因于肿瘤生长诱导的免疫抑制。在未接种疫苗的小鼠白血病病程的前半段，肿瘤排斥所必需的CD8+T细胞被激活而非抑制。在本报告中，我们质疑CD86（B7.2）或细胞因子粒细胞-巨噬细胞集落刺激因子（GM-CSF）、白细胞介素-4（IL-4）或肿瘤坏死因子-α（TNF-α）是否能提高AML细胞的疫苗接种潜力。细胞因子的选择基于它们单独以及联合引导CD34+细胞在体外分化为强大的抗原呈递树突状细胞的能力。我们的研究表明：（1）接种致白血病数量的经基因工程改造表达B7.2（B7.2-AML）或分泌GM-CSF、IL-4或TNF-α（GM-、IL-4-、TNF-α-AML）的AML细胞的小鼠不会发生白血病；（2）GM-AML细胞在亚致死剂量照射的SJL/J小鼠中具有致瘤性，但在瑞士裸鼠中没有，这表明肿瘤细胞的杀伤不是T细胞依赖性的；（3）用照射过的GM-AML细胞而非B7.2-、IL-4-或TNF-α-AML细胞制成的疫苗可引发白血病特异性的保护性和治疗性免疫；（4）在直接比较实验中，用照射过的GM-AML细胞接种比B7.1-AML更有效，在第2周时可治愈80%的白血病小鼠并使其延长存活20%，而B7.1-AML疫苗仅能治愈至1周。这些临床前数据强调GM-CSF基因免疫疗法值得在AML中进行临床评估。
