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或程序性死亡-1，它和CTLA-4一样，在活化的CD4和CD8 T细胞上上调，但通过Akt途径改变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细胞的生成，这些T细胞是裂解的、有功能的、分泌γ-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，我们建议在10名黑色素瘤患者的队列中进行I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，我们将进行另一项第一阶段研究，研究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。与公共健康相关：程序性死亡-1(PD-1)是在免疫T细胞表面发现的，这些T细胞已经被激活或打开，导致免疫细胞功能下降。能够消除小鼠肿瘤的免疫T细胞表面有大量的PD-1，因此它们不再具有杀死肿瘤细胞的功能。通过在患有肿瘤的动物身上使用抗体来降低PD-1在这些免疫T细胞上的功能，可以提高对这些肿瘤的免疫力，但也会引起对正常组织的一种称为自身免疫的反应。在这笔赠款中，我们将进行一项临床试验，在这项试验中，10名患有广泛的IV期黑色素瘤的患者将接受越来越多的抗PD-1抗体和疫苗，以衡量联合治疗的副作用，并了解其耐受性。我们的最终目标是通过改变限制PD-1等癌症患者免疫的分子之间的相互作用，增强人类免疫细胞摧毁肿瘤的能力。

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 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. PUBLIC HEALTH RELEVANCE: Programmed Death-1 (PD-1) is found on the surface of immune T cells that have been activated, or "turned on", causing immune cells to decrease their function. Immune T cells that could eliminate tumors in mice have high amounts of PD-1 on their surface, so that they no longer function to kill tumor cells. Decreasing the function of PD-1 on those immune T cells by the use of antibodies in animals that have tumors has resulted in increased immunity to those tumors but also caused a reaction against normal tissues called auto-immunity. In this grant, we will perform a clinical trial in which groups of 10 patients with widespread stage IV melanoma will receive increasing amounts of the anti-PD-1 antibody with a vaccine to measure the side effects of the combination and find out how well tolerated it is. Our ultimate goal is to augment the ability of human immune cells to destroy tumor by altering the interaction of molecules that limit immunity in cancer patients like PD-1.