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

免疫疗法代表了前列腺癌治疗的一种有前途的方法。我们的最新数据 实验室（以及其他实验室）表明，由T细胞之间的相互作用介导的免疫检查点， 被称为PD-1的表面分子和癌细胞上的分子B7-H1可以抑制抗肿瘤免疫 反应因此，使用针对PD-1的单克隆抗体阻断这种相互作用可能会发挥重要作用。 前列腺癌的治疗方法我们的研究小组还表明， 单核细胞增生李斯特菌（LM）显示出与PD-1 / B7-H1检查点阻断的显著协同作用。因此，在本发明中， 我们提出了一个I期临床试验，将这两种药物联合用于前列腺癌患者。因为疾病 负担在免疫治疗的结果中起着重要作用，我们选择了针对具有最小 疾病，即因高危疾病接受过放射治疗的男性。两名特工 这些数据目前处于第一阶段测试，这些数据将用于微调组合方法。 该试验包括几个关键的免疫相关性，以检验中心假设，即 PD-1阻断和基于PSCA特异性LM的疫苗接种将“破坏耐受性”并导致免疫缺陷。 前列腺中活化的CDS T细胞的积累。如果成功且耐受性良好， 将启动具有相关临床终点的II期试验。

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.