Blockade of the Immune Checkpoint Mediated by B7-H1 in Men with Prostate Cancer

免疫疗法是前列腺癌治疗的一种很有前途的方法。来自我们的最新数据 实验室(以及其他实验室)表明，免疫检查点由T细胞之间的相互作用介导 癌细胞表面分子PD-1和B7-H1可抑制抗肿瘤免疫 回应。因此，使用针对PD-1的单抗阻断这种相互作用可能起到 在前列腺癌治疗中的作用。我们的小组还表明，基于减毒的抗癌疫苗 单核细胞增多性李斯特菌(Lm)与阻断PD-1/B7-H1检查点有显著的协同作用。因此， 我们建议将这两种药物联合用于前列腺癌男性患者的I期试验。因为疾病 负担对免疫治疗的结果起着重要作用，我们选择了针对男性的最低限度 疾病，即因高危疾病接受过放射治疗的男性。受雇的两名特工 以下是目前正在进行的第一阶段测试，这些数据将用于微调组合方法。 这项试验包括几个关键的免疫相关因素，以检验核心假设，即 PD-1阻断和PSCA特异性LM疫苗接种将“打破耐受性”，并导致 活化的CDS T细胞在前列腺中积聚。如果成功并得到很好的容忍，将是一个更大的阶段 将启动有关临床终点的试验。

Immunotherapy represents a promising approach to prostate cancer treatment. Recent data from our laboratory (as well as others) shows that the immune checkpoint mediated by interactions between the T cell surface molecule known as PD-1 and the molecule B7-H1 on cancer cells can inhibit an anti-tumor immune response. Thus, blockade of this interaction using monoclonal antibodies directed against PD-1 may play a role in prostate cancer treatment. Our group has also shown that anti-cancer vaccines based on attenuated Listeria Monocytogenes (LM) show a striking synergy with blockade of the PD-1 / B7-H1 checkpoint. Thus, we propose a Phase I trial combining these two agents for men with prostate cancer. Because disease burden plays a major role in the outcome of immunotherapy, we have chosen to target men with minimal disease, i.e. men who have undergone radiation therapy for high-risk disease. Both of the agents employed here are currently in Phase I testing, and those data will be used to fine-tune the combinatorial approach. The trial includes several critical immune correlates to test the central hypothesis that the combination of PD-1 blockade and PSCA-specific LM-based vaccination will "break tolerance" and result in the accumulation of activated CDS T cells in the prostate gland. If successful and well tolerated, a larger phase II trial with relevant clinical endpoints will be initiated.