PD-1 Abrogation and Immunity in Melanoma

我们在分子水平上对T细胞激活的理解的进步使T细胞的操纵成为可能 癌症患者的细胞调节。一种新发现的参与T细胞调节的分子是PD-1或 程序性死亡-1，与CTLA-4一样，上调活化的CD4和CD8T细胞，但功能 通过Akt通路改变T细胞中的T细胞受体信号。一种针对PD-1的人源性抗体 在动物肿瘤模型中已显示其具有强大的抗肿瘤活性 单独或与疫苗联合使用。黑色素瘤患者PBMC的体外实验表明 抗体介导的PD-1去除增加了抗原特异性T细胞的产生，这些T细胞是溶解的 功能性的、分泌伽马干扰素的效应细胞。PD-1抗体增加了细胞在 表达CD107a，亲和力增强，抗原后CD8细胞增殖增加 暴露，促进细胞存活。PD-1抗体也能克服对T细胞增殖的抑制 这发生在自然T调节细胞存在的情况下。当PD-1阻滞剂与CTLA-4联合应用时 阻断在动物体内模型中有相加甚至协同的抗肿瘤作用。当两者都存在时 用人黑色素瘤特异性T细胞体外去除分子，产生抗原特异性 功能性T细胞明显增加。基于这些广泛的数据，我们建议执行一个阶段 用多肽疫苗在10例黑色素瘤队列中递增抗PD-1抗体剂量的试验 每个患者的毒性终点、MTD的定义以及免疫和其他 在队列之间进行代用检测。在重复接种PD-1抗体后，疫苗可 最佳刺激免疫力和良好的耐受性，我们将进行另一个阶段的研究 多肽疫苗联合PD-1和CTLA-4清除抗体治疗慢性粒细胞白血病 耐化疗的转移性黑色素瘤。

Advances in our understanding of T cell activation at a molecular level have permitted the manipulation of T cell regulation in cancer patients. A newly discovered molecule involved in T cell regulation is PD-1 or Programmed Death-1, which like CTLA-4 is upregulated on activated CD4 and CD8 T cells but functions through Akt pathways to alter T cell receptor signaling in T cells. A human antibody directed against PD-1 which abrogates its function has been shown in animal tumor models to have potent anti-tumor activity alone and in combination with vaccines. In vitro experiments with melanoma patient PBMC indicated that antibody mediated PD-1 abrogation increased the generation of antigen specific T cells that were lytic, functional, gamma-interferon secreting effector cells. PD-1 antibody increased the proportion of cells that expressed CD107a, augmented avidity and caused an increase in proliferating CD8 cells after antigen exposure, promoting cell survival. PD-1 antibody could also overcome the inhibition of T cell proliferation that occurred in the presence of natural T regulatory cells. When PD-1 blockade was combined with CTLA-4 blockade in vivo in animal models there was an additive or even synergistic anti-tumor effect. When both molecules were abrogated in vitro with human melanoma specific T cells, generation of antigen specific functional T cells was markedly increased. Based on those extensive data, we propose to perform a phase I trial of escalating doses of anti-PD-1 antibody with a multi-peptide vaccine in cohorts of 10 melanoma patients each with endpoints of toxicity, definition of an MTD and comparison of immune and other surrogate assays between cohorts. After a dose of PD-1 antibody given repetitively with a vaccine that optimally stimulates immunity and is well tolerated is defined, we will perform another phase I study of the combination of PD-1 and CTLA-4 abrogating antibodies with a multi-peptide vaccine in patients with chemotherapy resistant metastatic melanoma.