Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models.
Temozolomide does not impair gene therapy-mediated antitumor immunity in syngeneic brain tumor models.
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DOI：
10.1158/1078-0432.ccr-13-2140
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Castro MG
中科院分区：
文献类型：
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作者：
Candolfi M;Yagiz K;Wibowo M;Ahlzadeh GE;Puntel M;Ghiasi H;Kamran N;Paran C;Lowenstein PR;Castro MG
多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑癌。替莫唑胺（TMZ）化疗显著延长GBM患者的生存期。然而，3年生存率仍约为5%。在本文中，我们将表达Flt 3L的腺病毒载体（Ad-Flt 3L）与全身性TMZ的肿瘤内施用相结合，以评估其对治疗功效的影响。携带颅内GBM或转移性黑素瘤的野生型或免疫缺陷小鼠用单独或与条件细胞毒性酶胸苷激酶（Ad-TK）组合的Ad-Flt 3L的瘤内注射治疗，随后全身施用更昔洛韦和TMZ。我们监测存活率并测量肿瘤浸润免疫细胞。虽然单独使用TMZ治疗导致中位生存期略有改善，但当与基因治疗介导的免疫治疗联合使用时，它显着增加了荷瘤小鼠的生存期。肿瘤内同时给予Ad-TK进一步增强了抗肿瘤作用，导致所有肿瘤模型的长期生存率为50-70%。虽然TMZ降低了肿瘤中T细胞的含量，但这并不影响治疗效果。Ad-Flt 3L +Ad-TK+TMZ的抗肿瘤作用需要完整的免疫系统，因为当给予缺乏淋巴细胞或树突状细胞的KO小鼠时，治疗失败。我们的研究结果挑战了化疗导致免疫抑制状态的概念，这种状态会损害免疫系统产生有效抗肿瘤反应的能力。我们的工作表明，TMZ不抑制抗肿瘤免疫，并支持其与免疫介导的治疗组合的临床实施。
Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Chemotherapy with temozolomide (TMZ) significantly prolongs the survival of GBM patients. However, the 3-year survival is still ~5%. Herein we combined intratumoral administration of an adenoviral vector expressing Flt3L (Ad-Flt3L) with systemic TMZ in order to assess its impact on therapeutic efficacy. Wild type or immunodeficient mice bearing intracranial GBM or metastatic melanoma were treated with an intratumoral injection of Ad-Flt3L alone or in combination with the conditionally cytotoxic enzyme thymidine kinase (Ad-TK), followed by systemic administration of ganciclovir and TMZ. We monitored survival and measured the tumor-infiltrating immune cells. While treatment with TMZ alone led to a small improvement in median survival, when used in combination with gene therapy-mediated immunotherapy it significantly increased the survival of tumor-bearing mice. The anti-tumor effect was further enhanced by concomitant intratumoral administration of Ad-TK, leading to 50–70% long-term survival in all tumor models. Although TMZ reduced the content of T cells in the tumor, this did not affect the therapeutic efficacy. The anti-tumor effect of Ad-Flt3L+Ad-TK+TMZ required an intact immune system, since the treatment failed when administered to KO mice that lacked lymphocytes or dendritic cells. Our results challenge the notion that chemotherapy leads to a state of immune-suppression which impairs the ability of the immune system to mount an effective anti-tumor response. Our work indicates that TMZ does not inhibit antitumor immunity and supports its clinical implementation in combination with immune-mediated therapies.