CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model.
CpG-1826 immunotherapy potentiates chemotherapeutic and anti-tumor immune responses to metronomic cyclophosphamide in a preclinical glioma model.
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DOI：
10.1016/j.canlet.2015.11.029
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发表时间：
2016-04-01
期刊：
影响因子：
9.7
通讯作者：
Waxman DJ
中科院分区：
文献类型：
--
作者：
Jordan M;Waxman DJ
在几种神经胶质瘤模型中，按间歇性节律给药环磷酰胺可诱导强烈的免疫依赖性消退。在这里，我们研究免疫原性化疗是否可以通过与免疫刺激性TLR9激动剂CpG-1826相结合来增强。CpG-1826治疗GL261胶质瘤移植到免疫活性小鼠体内，导致肿瘤生长延迟，并伴随着巨噬细胞和B细胞的肿瘤募集增加。抗肿瘤反应因个体不同而不同，CpG-1826在约50%的治疗小鼠中诱导了强劲的肿瘤生长延迟。当CpG-1826与环磷酰胺联合治疗时，高和低CpG-1826反应的小鼠都显示出显著的改善。CpG-1826联合环磷酰胺(90 mg/kg)或节律环磷酰胺(45 mg/kg，间隔12天)治疗2个周期，肿瘤相关巨噬细胞、B细胞、树突状细胞和细胞毒性T细胞增加，T调节细胞不被诱导，GL261胶质瘤长期免疫记忆消退。B16F10黑色素瘤是一种低免疫原性肿瘤模型，对环磷酰胺/CpG-1826化疗免疫治疗也显示出增强的免疫和抗肿瘤反应，但与GL261肿瘤不同，它不会消退。因此，基于TLR9的免疫治疗可以有效地与免疫原性环磷酰胺治疗相结合，以增强基于免疫的抗肿瘤反应，即使在免疫原性较差的癌症模型中也是如此。
Cyclophosphamide administered on an intermittent metronomic schedule induces strong immune-dependent regression in several glioma models. Here we investigate whether this immunogenic chemotherapy can be potentiated by combination with the immune stimulatory TLR9 agonist CpG-1826. CpG-1826 treatment of GL261 gliomas implanted in immune competent mice induced tumor growth delay associated with increased tumor recruitment of macrophages and B cells. Anti-tumor responses varied between individuals, with CpG-1826 inducing robust tumor growth delay in ~50% of treated mice. Both high and low CpG-1826-responsive mice showed striking improvements when CpG-1826 was combined with cyclophosphamide treatment. Tumor-associated macrophages, B cells, dendritic cells, and cytotoxic T cells were increased, T regulatory cells were not induced, and long-term GL261 glioma regression with immune memory was achieved when CpG-1826 was combined with either single cyclophosphamide dosing (90 mg/kg) or metronomic cyclophosphamide treatment (two cycles at 45 mg/ kg, spaced 12-days apart). B16F10 melanoma, a low immunogenic tumor model, also showed enhanced immune and anti-tumor responses to cyclophosphamide/CpG-1826 chemoimmunotherapy, but unlike GL261 tumors, did not regress. TLR9-based immunotherapy can thus be effectively combined with immunogenic cyclophosphamide treatment to enhance immune-based anti-tumor responses, even in poorly immunogenic cancer models.