Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Center for Comparative Medicine, Baylor College of Medicine, Houston, TX, USA.
Cancer Immunol Immunother. 2020 Apr;69(4):641-651. doi: 10.1007/s00262-020-02493-z. Epub 2020 Feb 4.
Prostate cancer is a candidate for immunotherapy because cancer cells express tissue-specific proteins that can be therapeutic targets. However, immune checkpoint inhibitors and active immunization have performed poorly in clinical trials. We developed a novel virus-like particle (VLP) vaccine composed of bovine papillomavirus L1 protein engineered to display surface docking sites. We decorated VLPs with peptides encoding T cell epitopes from two prostate cancer-associated tumor antigens, prostate stem cell antigen (PSCA), and prostatic acid phosphatase (PAP-1 and PAP-2), and a neo-antigen, stimulator of prostatic adenocarcinoma-specific T cells (SPAS-1). The VLP vaccines induced a mean frequency of antigen-specific IFN-γ secreting CD8 + T cells of 2.9% to PSCA, 9.5% to SPAS-1, 0.03% to PAP-1, and 0.03% to PAP-2 in tumor-bearing TRAMP mice. We treated TRAMP mice at 19-20 weeks of age, when mice have advanced stages of carcinogenesis, with either VLP vaccine, anti-PD1 antibody, or combination immunotherapy. The VLP vaccine alone or in combination with anti-PD1 antibody significantly reduced tumor burden, while anti-PD1 antibody had a modest non-significant therapeutic effect. All treatments significantly increased CD3 + and CD8 + T cell infiltration into tumor tissue compared to control mice, and combination therapy resulted in significantly greater CD3 + and CD8 + T cell infiltration than monotherapy. Reduction in tumor burden in vaccine-treated mice was inversely correlated with CD8 + T cell numbers in tumor tissue. No other immunotherapy has shown efficacy in this animal model of advanced prostate cancer, making bovine papillomavirus VLPs an attractive vaccine technology to test in patients with metastatic prostate cancer.
前列腺癌是免疫疗法的候选者，因为癌细胞表达组织特异性蛋白，这些蛋白可以作为治疗靶点。然而，免疫检查点抑制剂和主动免疫在临床试验中的效果不佳。我们开发了一种新型的病毒样颗粒（VLP）疫苗，由牛乳头瘤病毒 L1 蛋白组成，经过工程改造后可显示表面对接位点。我们用编码两种与前列腺癌相关肿瘤抗原的 T 细胞表位的肽来装饰 VLP，这两种抗原是前列腺干细胞抗原（PSCA）和前列腺酸性磷酸酶（PAP-1 和 PAP-2），以及一个新抗原，前列腺腺癌特异性 T 细胞刺激物（SPAS-1）。在荷瘤 TRAMP 小鼠中，VLP 疫苗诱导针对 PSCA 的抗原特异性 IFN-γ 分泌 CD8+T 细胞的平均频率为 2.9%，针对 SPAS-1 的为 9.5%，针对 PAP-1 的为 0.03%，针对 PAP-2 的为 0.03%。我们在 19-20 周龄时用 VLP 疫苗、抗 PD1 抗体或联合免疫疗法治疗 TRAMP 小鼠，此时小鼠已经处于致癌的晚期阶段。单独使用 VLP 疫苗或与抗 PD1 抗体联合使用可显著降低肿瘤负担，而抗 PD1 抗体的治疗效果则适度且无统计学意义。与对照组相比，所有治疗方法均显著增加了肿瘤组织中 CD3+和 CD8+T 细胞的浸润，联合治疗导致 CD3+和 CD8+T 细胞的浸润显著高于单药治疗。疫苗治疗小鼠的肿瘤负担减少与肿瘤组织中 CD8+T 细胞数量呈负相关。在这种晚期前列腺癌的动物模型中，没有其他免疫疗法显示出疗效，这使得牛乳头瘤病毒 VLPs 成为一种有吸引力的疫苗技术，可以在转移性前列腺癌患者中进行测试。
