SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.
SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.
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DOI：
10.1158/0008-5472.can-14-1768-a
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发表时间：
2014-11-15
期刊：
影响因子：
11.2
通讯作者：
Shirwan H
中科院分区：
文献类型：
--
作者：
Srivastava AK;Dinc G;Sharma RK;Yolcu ES;Zhao H;Shirwan H
基于肿瘤相关抗原（TAA）的疫苗由于其免疫原性较弱以及在晚期肿瘤中活跃的各种免疫逃避机制，其治疗效果有限。为了克服这些限制，我们评估了 T 细胞共刺激分子 SA-4-1BBL 与 TLR4 激动剂单磷酰脂质 A (MPL) 的组合作为新型疫苗佐剂系统。在 HPV 诱导癌症的 TC-1 小鼠同种异体移植模型中，单次施用这种与 HPV E7 蛋白的组合佐剂可在所有荷瘤小鼠中引起肿瘤排斥。就其本身而言，SA-4-1BBL 在这种情况下的表现优于 MPL。针对已形成的肿瘤，两次疫苗接种足以引起大多数小鼠的排斥反应。在Lewis肺癌的转移模型中，用SA-4-1BBL/MPL接种TAA生存素对肺转移产生了优异的疗效。 SA-4-1BBL/MPL 的治疗功效是在没有可检测到的毒性的情况下实现的，与增强的 DC 激活、CD8+ T 细胞功能以及瘤内 CD8+ T 效应细胞与 CD4+ FoxP3+ T 调节细胞的比例增加相关。出乎意料的是，单独使用 MPL 与这些 T 细胞群的不利瘤内比例相关，导致疗效不佳。 MPL单一疗法的功效通过消除T调节细胞而恢复，而消除CD8+T细胞则消除了其与SA-4-1BBL联合疗法的功效。机制研究表明，IFN-γ 在支持 SA-4-1BBL/MPL 的治疗效果中发挥着关键作用。总而言之，我们的结果为基于 TAA 的癌症疫苗使用强大的新佐剂系统提供了临床前概念证明。
Vaccines based on tumor-associated antigens (TAA) have limited therapeutic efficacy due to their weak immunogenic nature and the various immune evasion mechanisms active in advanced tumors. In an effort to overcome these limitations, we evaluated a combination of the T cell co-stimulatory molecule SA-4-1BBL with the TLR4 agonist monophosphoryl lipid A (MPL) as a novel vaccine adjuvant system. In the TC-1 mouse allograft model of HPV-induced cancer, a single administration of this combination adjuvant with HPV E7 protein caused tumor rejection in all tumor-bearing mice. On its own, SA-4-1BBL outperformed MPL in this setting. Against established tumors, two vaccinations were sufficient to elicit rejection in the majority of mice. In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced DC activation, CD8+ T cell function and an increased intratumoral ratio of CD8+ T effector cells to CD4+FoxP3+ T regulatory cells. Unexpectedly, use of MPL on its own was associated with unfavorable intratumoral ratios of these T cell populations resulting in suboptimal efficacy. The efficacy of MPL monotherapy was restored by depletion of T regulatory cells, whereas eliminating CD8+ T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFN-γ played a critical role in supporting the therapeutic effect of SA-4-1BBL/MPL. Taken together, our results offer a preclinical proof of concept for the use of a powerful new adjuvant system for TAA-based cancer vaccines.