Vaccination for Invasive Canine Meningioma Induces In Situ Production of Antibodies Capable of Antibody-Dependent Cell-Mediated Cytotoxicity
Vaccination for Invasive Canine Meningioma Induces In Situ Production of Antibodies Capable of Antibody-Dependent Cell-Mediated Cytotoxicity
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DOI：
10.1158/0008-5472.can-12-3366
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Ohlfest, John R.
中科院分区：
文献类型：
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作者：
Andersen, Brian M.;Pluhar, G. Elizabeth;Ohlfest, John R.
恶性和非典型脑膜瘤对标准治疗有抵抗力，预后差。尽管在用治疗性疫苗治疗其他肿瘤方面取得了进展，但这种方法尚未在这些肿瘤中进行临床前或临床测试。自发性犬脑膜瘤是一种临床上有意义但未充分利用的模型，用于临床前测试侵袭性人类脑膜瘤的新策略。我们用手术和疫苗免疫疗法治疗了11只脑膜瘤荷瘤犬，疫苗免疫疗法由自体肿瘤细胞裂解物和toll样受体配体组成。治疗耐受性良好，只有一只狗有肿瘤生长需要干预，平均随访585天。在2例患者的外周血中检测到IFN-γ表达T细胞，但所有犬均出现疫苗诱导的肿瘤反应性抗体应答。抗体反应是多克隆的，识别细胞内和细胞表面抗原，和HSP 60被确定为一个共同的抗原。肿瘤反应性抗体结合同种异体犬和人脑膜瘤，显示跨品种和物种的共同抗原。组织学分析显示，与治疗前样品相比，治疗后分泌抗体的浆细胞大量浸润到肿瘤周围的大脑中。肿瘤反应性抗体能够诱导抗体依赖性细胞介导的对自体和同种异体肿瘤细胞的细胞毒性。这些数据显示了疫苗免疫疗法在大型人类脑膜瘤动物模型中的可行性和免疫学疗效，并保证了进一步向人体试验发展。Cancer Res; 73（10）; 2987-97. (C)2013年AACR。
Malignant and atypical meningiomas are resistant to standard therapies and associated with poor prognosis. Despite progress in the treatment of other tumors with therapeutic vaccines, this approach has not been tested preclinically or clinically in these tumors. Spontaneous canine meningioma is a clinically meaningful but underutilized model for preclinical testing of novel strategies for aggressive human meningioma. We treated 11 meningioma-bearing dogs with surgery and vaccine immunotherapy consisting of autologous tumor cell lysate combined with toll-like receptor ligands. Therapy was well tolerated, and only one dog had tumor growth that required intervention, with a mean follow up of 585 days. IFN-gamma-elaborating T cells were detected in the peripheral blood of 2 cases, but vaccine-induced tumor-reactive antibody responses developed in all dogs. Antibody responses were polyclonal, recognizing both intracellular and cell surface antigens, and HSP60 was identified as one common antigen. Tumor-reactive antibodies bound allogeneic canine and human meningiomas, showing common antigens across breed and species. Histologic analysis revealed robust infiltration of antibody-secreting plasma cells into the brain around the tumor in posttreatment compared with pretreatment samples. Tumor-reactive antibodies were capable of inducing antibody-dependent cell-mediated cytotoxicity to autologous and allogeneic tumor cells. These data show the feasibility and immunologic efficacy of vaccine immunotherapy for a large animal model of human meningioma and warrant further development toward human trials. Cancer Res; 73(10); 2987-97. (C) 2013 AACR.