The median (range) age of all patients was 61. 0 (3474) years. and 20 mg/kg. One durable complete Ribocil B response and two partial responses were observed. ConclusionsNivolumab at doses of 120 mg/kg was not associated with DLTs, and it was generally well tolerated at doses of up to 20 mg/kg in Japanese patients with advanced solid tumors. == Electronic supplementary material == The online version of this article (doi: 10. 1007/s10637-016-0411-2) contains supplementary material. Keywords: Phase I study, Nivolumab, Immune checkpoint inhibitor, Pharmacokinetics == Introduction == Cancer accounted for 330, 000 deaths in Japanapproximately 30% of all deathsin 2010 [1]. Despite advances in cancer treatment, Ribocil B the morbidity and mortality rates associated with some types of cancer are expected to continue to increase [2]. Immunotherapeutic agents, such as biologics, which use the bodys own immunity to eliminate tumors or directly target tumors, have been under investigation for several decades. In recent years, these agents have been included alongside surgery, radiation and chemotherapy in the treatment of many types of cancer [3, 4]. More recently, vaccine therapies using cancer antigens or dendritic cells have been studied, but their response rates were as low as 2 . 6%, partly because of the expression of molecules (e. g., cytokines and co-stimulators) that suppress immunological activity on regulatory lymphocytes and cancer cells themselves [5]. Programmed death-1 (PD-1) (also known as CD279) is a CD28 family receptor that is expressed on activated Ribocil B lymphocytes (T cells, B cells and NKT cells) and myeloid cells. PD-1 and its ligands Ribocil B defend against self-reactive effector T cells by promoting the development and function of regulatory T cells and directly inhibiting potentially pathogenic self-reactive peripheral T cells [6]. PD-1 ligands are expressed on antigen-presenting cells (APCs) and parenchymal cells. PD-1 ligands on APCs induce immunological tolerance by switching off autoreactive T cells, while ligands expressed on parenchymal cells suppress effector T cells, thus maintaining peripheral tolerance by preventing tissue destruction [7]. PD-1, its ligands (e. g., PD-L1), or both are overexpressed in many autoimmune diseases, including inflammatory bowel disease, rheumatoid arthritis and type 1 diabetes [6]. PD-1 deficiency in mice leads to the development of various autoimmune disorders, such as dilated cardiomyopathy associated with autoantibody production in BALB/c mice, systemic lupus erythematosus-like glomerular nephritis and arthritis in C57BL/6 mice, myocarditis associated with generation of autoantibody in MRL mice, and accelerated type 1 diabetes in non-obese diabetic mice, suggesting that PD-1 is involved in the suppression of autoimmune reactions [7, 8]. PD-L1 expression by tumor cells may induce and maintain regulatory T cells in the tumor, allowing tumor progression by enhanced suppression of antitumor T-cell Mouse monoclonal antibody to CaMKIV. The product of this gene belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This enzyme is a multifunctionalserine/threonine protein kinase with limited tissue distribution, that has been implicated intranscriptional regulation in lymphocytes, neurons and male germ cells responses [9]. In addition to APCs, PD-1 ligands are expressed in various human cancer tissues [9], and PD-L1 expression in resected cancer tissues was correlated with postoperative survival time in ovarian cancer [10], malignant melanoma [11], esophageal cancer [12], renal cell carcinoma (RCC) [13], pancreatic cancer [14], and urothelial cancer [15], for example. In an experiment using a murine cancer cell line, the PD-1 ligand-knockout murine cancer cell line (P815 cells) was attacked by cytotoxic T cells specific to this cancer cell line. Transfection of this cell line with PD-L1 decreased the cells susceptibility to cytotoxic T cells. In an autologous tumor-bearing model using the same PD-L1transfected cancer cell line, proliferation of the transplanted cancer cells was inhibited by antiPD-1 antibody [16]. These findings suggest that the PD-1/PD-1 ligand pathway is involved in cancer cell immunity, and that PD-1 inhibitors are expected to be useful anticancer agents [7]. Nivolumab (Ono Pharmaceutical developmental code: ONO-4538; Bristol-Myers Squibb [BMS] developmental code: BMS-936558; ex-Medarex developmental code: MDX-1106) is a fully human monoclonal antibody to human PD-1 that was co-developed by Ono Pharmaceutical Co., Ltd. and Medarex Inc. Nivolumab was well tolerated when administered.