Lin Jian Min, Li Betty, Rimmer Eric, VanRoey Melinda, Jooss Karin
Department of Preclinical Oncology, Cell Genesys Inc, South San Francisco, CA 94080, USA.
Exp Hematol. 2008 Mar;36(3):319-28. doi: 10.1016/j.exphem.2007.11.005.
Acute myeloid leukemia (AML) is a highly malignant neoplasm responsible for nearly 10,000 cancer-related deaths annually in the United States. Treatment options for elderly patients with AML remain limited. Standard regimens using cytarabine (cytosine arabinoside [AraC]), a nucleotide analogue, result in significant toxicity with poor overall response. Combination of a cytotoxic chemotherapy and tumor-specific immunotherapy has the potential to improve overall efficacy by inducing an anti-tumor immune response against minimal residual disease. The studies reported here were performed to evaluate the therapeutic benefit of combining a granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy with AraC treatment.
C57Bl/6 mice were challenged with C1498-luc cells intravenously and evaluated by in vivo imaging throughout the study to monitor the systemic progression of the tumor. Individual animals were euthanized when in vivo total photon counts exceeded 5 x 10(8) and/or when they were in poor clinical condition. Cytotoxicity assay was performed to evaluate effector function and flow cytometry was used for phenotyping of splenocytes from experimental animals.
Administration of GM-CSF-secreting tumor cell immunotherapy during AraC -induced cytopenia enhanced the anti-tumor efficacy of the immunotherapy, resulting in prolonged survival. AraC treatment did not negatively impact antigen-specific T-cell activation elicited by the immunotherapy and surviving animals treated with the combination demonstrated strong tumor-specific memory responses.
GM-CSF-secreting tumor cell immunotherapy in combination with AraC prolongs survival of tumor-bearing mice, with a median survival time of 61 days observed in mice treated with AraC alone and 90% of mice treated with the combination therapy still alive by day 150.
急性髓系白血病（AML）是一种高度恶性的肿瘤，在美国每年导致近10,000例癌症相关死亡。老年AML患者的治疗选择仍然有限。使用阿糖胞苷（胞嘧啶阿拉伯糖苷 [AraC]）的标准方案，一种核苷酸类似物，会导致显著的毒性且总体反应不佳。细胞毒性化疗与肿瘤特异性免疫疗法的联合有可能通过诱导针对微小残留病的抗肿瘤免疫反应来提高总体疗效。本文报道的研究旨在评估分泌粒细胞巨噬细胞集落刺激因子（GM-CSF）的肿瘤细胞免疫疗法与阿糖胞苷治疗联合的治疗益处。
C57Bl/6小鼠经静脉注射C1498-luc细胞进行攻击，并在整个研究过程中通过体内成像进行评估，以监测肿瘤的全身进展。当体内总光子计数超过5×10⁸和/或动物临床状况不佳时，对个体动物实施安乐死。进行细胞毒性测定以评估效应功能，流式细胞术用于对实验动物的脾细胞进行表型分析。
在阿糖胞苷诱导的血细胞减少期间给予分泌GM-CSF的肿瘤细胞免疫疗法可增强免疫疗法的抗肿瘤疗效，从而延长生存期。阿糖胞苷治疗并未对免疫疗法引发的抗原特异性T细胞活化产生负面影响，接受联合治疗的存活动物表现出强烈的肿瘤特异性记忆反应。
分泌GM-CSF的肿瘤细胞免疫疗法与阿糖胞苷联合可延长荷瘤小鼠的生存期，单独接受阿糖胞苷治疗的小鼠中位生存期为61天，而接受联合治疗的小鼠在第150天时90%仍然存活。
