Srivastava Abhishek K, Dinc Gunes, Sharma Rajesh K, Yolcu Esma S, Zhao Hong, Shirwan Haval
Institute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky.
Cancer Res. 2014 Nov 15;74(22):6441-51. doi: 10.1158/0008-5472.CAN-14-1768-A. Epub 2014 Sep 24.
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 costimulatory 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 human papilloma virus (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 dendritic cell 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 IFNγ 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.
基于肿瘤相关抗原（TAA）的疫苗由于其免疫原性较弱以及晚期肿瘤中活跃的各种免疫逃逸机制，治疗效果有限。为了克服这些局限性，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）的组合作为一种新型疫苗佐剂系统。在人乳头瘤病毒（HPV）诱导的癌症的TC - 1小鼠同种异体移植模型中，将这种组合佐剂与HPV E7蛋白单次给药可使所有荷瘤小鼠的肿瘤消退。在此情况下，单独使用SA - 4 - 1BBL的效果优于MPL。对于已形成的肿瘤，两次接种疫苗足以使大多数小鼠产生肿瘤排斥反应。在Lewis肺癌转移模型中，用SA - 4 - 1BBL/MPL接种TAA存活素对肺转移具有更好的疗效。SA - 4 - 1BBL/MPL在没有可检测到的毒性的情况下实现了治疗效果，这与树突状细胞活化增强、CD8(+) T细胞功能以及肿瘤内CD8(+) T效应细胞与CD4(+)FoxP3(+) T调节细胞比例增加相关。出乎意料的是，单独使用MPL与这些T细胞群体在肿瘤内的比例不理想有关，导致疗效欠佳。通过清除T调节细胞可恢复MPL单药治疗的疗效，而消除CD8(+) T细胞则消除了其与SA - 4 - 1BBL联合使用的疗效。机制研究表明，IFNγ在支持SA - 4 - 1BBL/MPL的治疗效果中起关键作用。综上所述，我们的结果为基于TAA的癌症疫苗使用一种强大的新佐剂系统提供了临床前概念验证。
