Gene immunotherapy in murine acute myeloid leukemia: Granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines
Gene immunotherapy in murine acute myeloid leukemia: Granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines
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DOI：
10.1182/blood.v91.1.222.222_222_230
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发表时间：
1998-01-01
期刊：
影响因子：
20.3
通讯作者：
Croop, JM
中科院分区：
文献类型：
--
作者：
Dunussi-Joannopoulos, K;Dranoff, G;Croop, JM
为了探索治疗急性髓系白血病(AML)的新方法，我们研究了共刺激和细胞因子基因免疫治疗在小鼠AML中的作用。我们以前已经证明，在白血病病程早期给予CD80转基因白血病细胞(B7.1-AML疫苗)可以治愈白血病小鼠，并且晚期给予B7.1-AML疫苗的失败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中，肿瘤排斥反应所必需的CD8(+)T细胞在白血病病程的前半段被激活而不是被抑制。在本报告中，我们质疑CD86(B7.2)或细胞因子粒-巨噬细胞集落刺激因子(GM-CSF)、白介素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。细胞因子的选择是基于它们的组合和单独作用，以及在体外引导CD34(+)细胞分化为强大的抗原提呈树突状细胞的能力。我们的研究表明：(1)用表达B7.2(B7.2-AML)或分泌GM-CSF、IL-4或TNF-α(GM-、IL-4、TNF-α-AML)的基因工程AML细胞免疫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小鼠中可产生肿瘤，但在瑞士NU/NU小鼠中不会发生肿瘤，表明肿瘤细胞的杀伤不依赖T细胞；(3)经照射的GM-AML细胞疫苗可诱导白血病特异性的保护性和治疗性免疫，而B7.2-、IL-4或TNF-α-AML细胞则不能；(4)在头对头比较实验中，照射的GM-AML细胞疫苗比B7.1-AML细胞更有效，可使白血病小鼠在2周时治愈80%和延长20%的生存时间，而B7.1-AML疫苗只能治愈1周。(C)1998年由美国血液病学会主办。
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. (C) 1998 by The American Society of Hematology.