PD-1 abrogation and immunity in melanoma

描述(由申请人提供)： 我们在分子水平上对T细胞激活的理解的进步使得在癌症患者中操纵T细胞调节成为可能。一个新发现的参与T细胞调节的分子是PD-1，它和CTLA-4一样，在活化的CD4和CD8T细胞上上调，但通过Akt通路改变T细胞中的T细胞受体信号。在动物肿瘤模型中，一种针对PD-1的人类抗体已经被证明具有强大的抗肿瘤活性，并与疫苗联合使用。对黑色素瘤患者外周血单个核细胞的体外实验表明，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细胞是裂解的、有功能的、分泌干扰素的效应细胞。PD-1抗体使抗原暴露后表达CD107a的细胞比例增加，亲和力增强，CD8细胞增殖增加，促进细胞存活。PD-1抗体还可以克服在自然T调节细胞存在下对T细胞增殖的抑制。在动物模型中，PD-1受体阻断剂与CTLA-4受体阻断剂联合应用，具有相加甚至协同的抗肿瘤作用。当这两个分子在体外与人黑色素瘤特异性T细胞一起被取消时，抗原特异性功能T细胞的生成显著增加。基于这些广泛的数据，研究人员建议在10名黑色素瘤患者的队列中进行一期试验，用多肽疫苗逐步增加抗PD-1抗体的剂量，每个患者都有毒性终点，MTD的定义，以及队列之间免疫和其他替代分析的比较。在定义了重复给予PD-1抗体的剂量后，研究人员将对PD-1和CTLA-4去除抗体与多肽疫苗在化疗耐药转移性黑色素瘤患者中的组合进行第二阶段研究。

DESCRIPTION (provided by applicant): 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, 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 peripheral blood mononuclear cell 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, the investigators propose to perform a Phase 1 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 a 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, the investigators will perform a Phase 2 study of the combination of PD-1 and CTLA-4 abrogating antibodies with a multi-peptide vaccine in patients with chemotherapy resistant metastatic melanoma.