Cappuccini Federica, Pollock Emily, Stribbling Stephen, Hill Adrian V S, Redchenko Irina
The Jenner Institute, University of Oxford, Roosevelt Drive Oxford, Oxford OX3 7DQ, United Kingdom.
Oncotarget. 2017 Jul 18;8(29):47474-47489. doi: 10.18632/oncotarget.17666.
The tumour-associated antigen 5T4 is an attractive target for cancer immunotherapy. However to date, reported 5T4-specific cellular immune responses induced by various immunisation platforms have been largely weak or non-existent. In the present study, we have evaluated a heterologous prime boost regime based on the simian adenovirus ChAdOx1 and modified vaccinia virus Ankara (MVA) expressing 5T4 for immunogenicity and tumour protective efficacy in a mouse cancer model. Vaccination-induced immune responses were strong, durable and attributable primarily to CD8+ T cells. By comparison, homologous MVA vaccination regimen did not induce detectable 5T4-specific T cell responses. ChAdOx1-MVA vaccinated mice were completely protected against subsequent B16 melanoma challenge, but in therapeutic settings this regime was only modestly effective in delaying tumour outgrowth. Concomitant delivery of the vaccine with monoclonal antibodies (mAbs) targeting immune checkpoint regulators LAG-3, PD-1 or PD-L1 demonstrated that the combination of vaccine with anti PD-1 mAb could significantly delay tumour growth and increase overall survival of tumour-bearing mice. Our findings support a translation of the combinatorial approach based on the heterologous ChAdOx1-MVA vaccination platform with immune checkpoint blockade into the clinic for the treatment of 5T4-positive tumours such as prostate, renal, colorectal, gastric, ovarian, lung cancer and mesothelioma.
肿瘤相关抗原5T4是癌症免疫治疗的一个有吸引力的靶点。然而，迄今为止，各种免疫接种平台诱导的5T4特异性细胞免疫反应大多较弱或不存在。在本研究中，我们评估了一种基于猿猴腺病毒ChAdOx1和表达5T4的改良痘苗病毒安卡拉（MVA）的异源初免-加强方案在小鼠癌症模型中的免疫原性和肿瘤保护效果。疫苗接种诱导的免疫反应强烈、持久，主要归因于CD8+T细胞。相比之下，同源MVA疫苗接种方案未诱导可检测到的5T4特异性T细胞反应。ChAdOx1-MVA疫苗接种的小鼠对随后的B16黑色素瘤攻击具有完全保护作用，但在治疗环境中，该方案在延迟肿瘤生长方面仅具有适度的效果。将疫苗与靶向免疫检查点调节因子LAG-3、PD-1或PD-L1的单克隆抗体（mAb）联合使用表明，疫苗与抗PD-1 mAb联合使用可显著延迟肿瘤生长并提高荷瘤小鼠的总生存率。我们的研究结果支持将基于异源ChAdOx1-MVA疫苗接种平台与免疫检查点阻断的联合方法转化到临床，用于治疗5T4阳性肿瘤，如前列腺癌、肾癌、结直肠癌、胃癌、卵巢癌、肺癌和间皮瘤。
