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细胞活化的理解的进展已经允许在癌症患者中操纵T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，它与CTLA-4一样在活化的CD 4和CD 8 T细胞上上调，但通过Akt途径发挥作用，改变T细胞中的T细胞受体信号传导。已经在动物肿瘤模型中显示，针对PD-1的消除其功能的人抗体单独和与疫苗组合具有有效的抗肿瘤活性。用黑素瘤患者PBMC进行的体外实验表明，抗体介导的PD-1消除增加了抗原特异性T细胞的产生，所述T细胞是溶解性的、功能性的、分泌γ-干扰素的效应细胞。PD-1抗体增加了表达CD 107 a的细胞比例，增强了亲合力，并在抗原暴露后引起增殖的CD 8细胞增加，促进了细胞存活。PD-1抗体还可以克服在天然调节性T细胞存在下发生的T细胞增殖抑制。当PD-1阻断与CTLA-4阻断在动物模型中体内组合时，存在累加或甚至协同抗肿瘤作用。当这两种分子在体外与人黑色素瘤特异性T细胞一起被废除时，抗原特异性功能性T细胞的产生显著增加。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递增剂量的抗PD-1抗体与多肽疫苗的I期试验，每个队列具有毒性终点，MTD的定义以及队列之间的免疫和其他替代测定的比较。在确定PD-1抗体与最佳刺激免疫力且耐受性良好的疫苗重复给药的剂量后，我们将在化疗耐药转移性黑色素瘤患者中进行PD-1和CTLA-4消除抗体与多肽疫苗组合的另一项I期研究。 公共卫生相关性：程序性死亡-1（PD-1）存在于免疫T细胞的表面，这些细胞已被激活或“打开”，导致免疫细胞功能下降。可以消除小鼠肿瘤的免疫T细胞表面具有大量的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中使用抗体来降低PD-1对这些免疫T细胞的功能，导致对这些肿瘤的免疫力增加，但也引起了对正常组织的反应，称为自身免疫。在这项资助中，我们将进行一项临床试验，其中10名患有广泛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，以测量组合的副作用，并找出它的耐受性。我们的最终目标是通过改变限制癌症患者免疫力的分子（如PD-1）的相互作用来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.