PD-1 Abrogation and Immunity in Melanoma

我们在分子水平上对T细胞活化的理解的进展允许操纵T细胞。 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 与CTLA-4一样，程序性死亡-1在活化的CD 4和CD 8 T细胞上上调，但功能 通过Akt途径改变T细胞中的T细胞受体信号传导。针对PD-1的人抗体 已经在动物肿瘤模型中显示具有有效的抗肿瘤活性 单独使用或与疫苗联合使用。用黑素瘤患者PBMC进行的体外实验表明， 抗体介导的PD-1消除增加了裂解的抗原特异性T细胞的产生， 功能性γ-干扰素分泌效应细胞。PD-1抗体增加了细胞的比例， 表达CD 107 a，增强亲和力，并引起抗原后增殖的CD 8细胞增加， 暴露，促进细胞存活。PD-1抗体也能克服T细胞增殖抑制 在自然调节性T细胞存在的情况下发生。当PD-1阻断剂与CTLA-4联合使用时， 在动物模型中，体内阻断存在累加甚至协同的抗肿瘤作用。当两 分子在体外用人黑素瘤特异性T细胞消除，产生抗原特异性 功能性T细胞显著增加。基于这些广泛的数据，我们建议执行一个阶段 在10个黑色素瘤队列中使用递增剂量的抗PD-1抗体和多肽疫苗的I项试验 每个患者都有毒性终点，MTD的定义以及免疫和其他 队列之间的替代试验。在与疫苗一起重复给予一剂PD-1抗体后， 最佳刺激免疫力，并具有良好的耐受性，我们将进行另一项I期研究， 在患有CTLA-4的患者中使用PD-1和CTLA-4消除抗体与多肽疫苗的组合 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.