Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the B16 melanoma mouse model and immune correlates.
Combination of alphavirus replicon particle-based vaccination with immunomodulatory antibodies: therapeutic activity in the B16 melanoma mouse model and immune correlates.
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DOI：
10.1158/2326-6066.cir-13-0220
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发表时间：
2014-05
影响因子：
10.1
通讯作者：
Merghoub T
中科院分区：
文献类型：
--
作者：
Avogadri F;Zappasodi R;Yang A;Budhu S;Malandro N;Hirschhorn-Cymerman D;Tiwari S;Maughan MF;Olmsted R;Wolchok JD;Merghoub T
诱导对自身抗原的有效免疫反应仍然是肿瘤免疫学的主要挑战。我们已经证明，基于甲型病毒复制子颗粒(VRP)的疫苗可以激活对酪氨酸酶相关蛋白-2(Trp2)黑色素瘤抗原的强大细胞和体液免疫，在严格的小鼠模型中提供预防和治疗效果。在此，我们报道了该疫苗与拮抗型抗CTLA-4或激动型抗GITR免疫调节单抗(MAbs)联合使用可提高疫苗的免疫原性和效力。在具有挑战性的治疗环境中，VRP-Trp2联合抗GITR或抗CTLA-4单抗分别可使90%和50%的小鼠肿瘤完全消退。这些单抗在启动针对疫苗编码抗原的适应性免疫反应方面具有类似的佐剂作用，与单独接种疫苗相比，Trp2特异性CD8+T细胞反应和循环中的单抗分别增强了约4倍和2倍。此外，两种单抗均可增加CD8+T细胞的浸润率，抗CTLA4mAb也可增加肿瘤内表达阴性共刺激分子程序性死亡1(PD-1)的−T细胞的数量。在这些细胞上同时表达GITR表明它们可能受抗GITR单抗控制，从而潜在地解释了它们在两种处理条件下的差异积累。这些发现表明，将免疫调节性单抗与基于甲型病毒的抗癌疫苗相结合，可以在严格的小鼠模型中提供治疗性抗肿瘤免疫反应，这表明在临床试验中具有潜在的实用价值。他们还表明，肿瘤浸润性CD4+Foxp3、−、PD-1+T细胞可能会影响免疫调节治疗的结果。
Induction of potent immune responses to self-antigens remains a major challenge in tumor immunology. We have shown that a vaccine based on alphavirus replicon particles (VRP) activates strong cellular and humoral immunity to tyrosinase related protein-2 (TRP2) melanoma antigen, providing prophylactic and therapeutic effects in stringent mouse models. Here we report that the immunogenicity and efficacy of this vaccine is increased in combination with either antagonist anti-CTLA-4 or agonist anti-GITR immunomodulatory monoclonal antibodies (mAbs). In the challenging therapeutic setting, VRP-TRP2 plus anti-GITR or anti-CTLA-4 mAb induced complete tumor regression respectively in 90% and 50% of mice. These mAbs had similar adjuvant effects in priming an adaptive immune response against the vaccine-encoded antigen, augmenting respectively ~4- and 2-fold the TRP2-specific CD8+ T-cell response and circulating Abs, compared to the vaccine alone. Furthermore, while both mAbs increased the frequency of tumor-infiltrating CD8+ T cells, anti-CTLA-4 mAb also increased the quantity of intra-tumor CD4+Foxp3− T cells expressing the negative co-stimulatory molecule programmed death-1 (PD-1). Concurrent GITR expression on these cells suggests that they might be controlled by anti-GITR mAbs, thus potentially explaining their differential accumulation under the two treatment conditions. These findings indicate that combining immunomodulatory mAbs with alphavirus-based anti-cancer vaccines can provide therapeutic anti-tumor immune responses in a stringent mouse model, suggesting potential utility in clinical trials. They also indicate that tumor-infiltrating CD4+Foxp3−PD-1+ T cells may affect the outcome of immunomodulatory treatments.