Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors.
Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors.
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DOI：
10.1097/cji.0b013e3182562d59
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发表时间：
2012-06
期刊：
影响因子：
--
通讯作者：
Curry WT Jr
中科院分区：
文献类型：
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作者：
Agarwalla P;Barnard Z;Fecci P;Dranoff G;Curry WT Jr
恶性胶质瘤是一种无法治愈的疾病，中位生存期相对较短。几项临床试验表明，免疫疗法与疫苗接种是一种安全和可能有效的延长生存期的方法。基于抗体的CTLA-4对T淋巴细胞连接的阻断与癌症动物模型和晚期黑色素瘤患者中增强的抗肿瘤免疫相关。我们假设表达GM-CSF的全胶质瘤细胞疫苗接种和CTLA-4阻断的序贯疗法是治疗已建立的颅内胶质瘤的有效策略。将GL 261胶质瘤细胞注射到同基因C57/BL 6小鼠的右额叶中。在肿瘤植入后第3、6和9天，用皮下注射经辐照的表达GMCSF的GL 261细胞处理小鼠。还在第3、6和9天或第12、15和18天用腹膜内注射抗CTLA-4单克隆抗体（mAb）处理小鼠。跟踪动物的存活情况。在第22天收获脾细胞用于ELISP 0 T测定。用高剂量CTLA-4阻断剂早期治疗已建立的颅内胶质瘤与GL 261荷瘤小鼠的存活率增加相关。与对照处理的小鼠相比，用抗CTLA-4 mAb的后期处理没有显著改善存活率。早期疫苗接种后，随后CTLA-4阻断与显著改善的生存率相比，单独治疗和增强肿瘤特异性免疫，如干扰素-γ ELISPOT所测量的。表达GM-CSF的放射性胶质瘤细胞和CTLA-4阻断剂的序贯免疫治疗协同延长了已建立的颅内胶质瘤小鼠的存活率。
Malignant glioma is an incurable disease with a relatively short median survival. Several clinical trials have demonstrated that immunotherapy with vaccination is a safe and possibly effective way of prolonging survival. Antibody-based blockade of CTLA-4 ligation on T lymphocytes is associated with enhanced antitumor immunity in animal models of cancer and in patients with advanced melanoma. We hypothesized that sequential therapy with GM-CSF - expressing whole glioma cell vaccination and CTLA-4 blockade is an effective strategy for treating established intracranial gliomas. GL261 glioma cells were injected into the right frontal lobes of syngeneic C57/BL6 mice. At days 3, 6, and 9 after tumor implantation, mice were treated with subcutaneous injection of irradiated GMCSF-expressing GL261 cells. Mice were also treated with intraperitoneal injection of anti-CTLA-4 monoclonal antibodies (mAbs), either at days 3, 6, and 9 or days 12, 15, and 18. Animals were followed for survival. Splenocytes were harvested at day 22 for use in ELISPOT assays. Early treatment of established intracranial gliomas with high-dose CTLA-4 blockade was associated with increased survival in GL261-bearing mice. Later treatment with anti-CTLA-4 mAbs did not significantly improve survival compared to control-treated mice. Early vaccination followed by subsequent CTLA-4 blockade was associated with significantly improved survival versus either treatment alone and intensified tumor-specific immunity as measured by interferon-gamma ELISPOT. Sequential immunotherapy with GM-CSF-expressing irradiated glioma cells and CTLA-4 blockade synergistically prolongs survival in mice bearing established intracranial gliomas.