A large multicenter phase III trial with atezolizumab that aims to recruit 767 patients with locally advanced or mUC who have failed prior platinum-based chemotherapy is currently underway (“type”:”clinical-trial”,”attrs”:”text”:”NCT02302807″,”term_id”:”NCT02302807″NCT02302807). Harnessing the rational combination of immunostimulatory BCG therapy with inhibition of immunosuppressive targets such as the PD-1 axis is being studies across several clinical trials currently. the American Society for Clinical Oncology. Results: In heavily pre-treated UC, trials are suggesting objective response rates above 30% . These impressive results are seen across multiple different tumour types, especially those with high burden of DNA level mutations. Microcystin-LR Identification of prognostic biomarkers is currently under investigation, in order to improve patient selection. Interestingly, response to PD-1 directed therapy is seen even in patients with no evidence of PD-1 positivity on immunohistochemistry. This has led to the development of enhanced biomarkers including assessing DNA mutation rates and immune gene signatures, to improve patient selection. Conclusions: Immune checkpoint blockade is an exciting cancer treatment modality which is demonstrating impressive clinical results across multiple tumour types. For UC, anti-PD directed therapy represents a much Microcystin-LR needed treatment in the metastatic, post chemotherapy context. Potential for these agents to have clinical Microcystin-LR utility in non-metastatic UC is still to be assessed. and subunits of MHC-I) [7]. However, this process is dynamic and represents an equilibrium between the ability of the immune system to identify and eliminate malignant cells, and the ability of the malignant cells to escape such recognition. The mechanism of tumour cell (TC) escape may be due to decreases in neo-antigen presentation, the establishment of a cytokine milieu that promotes an immunosuppressive tumour microenvironment (TME), or up-regulation of negative co-signals which prevent effective T-cell activation, thus allowing ongoing tumour growth [8]. Together, this process is described as the cancer-immunity cycle [9]. TCs interact with tumour associated immune cells (TAIC) within the TME to orchestrate successful immune escape [10]. Cell-mediated immunity employs inhibitory co-regulatory signaling in order to maintain self-tolerance, an evolutionary conserved mechanism of preventing damage to host tissues when the immune system is activated in Microcystin-LR response to tumour or infection [11]. Presently, most cancer immunotherapy strategies aim at restoring T-cell-mediated anti-tumour activity, in essence harnessing the patients own immune system Microcystin-LR for therapeuticbenefit. The three checkpoint molecules that have been studied most extensively and have become clinically important targets of drug therapy are cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death (PD)-1 and PD-ligand-1 (PD-L1). Ipilimumab (anti-CTLA-4), nivolumab and pembrolizumab (anti-PD-1), and atezolizumab (anti-PD-L1) are the leading examples of a series of monoclonal antibodies under development that specifically block the inhibitory receptor-ligand interaction at the T-cell membrane. By inhibiting the immune checkpoint, these drugs permit activation of the immune response to TCs. Ipilimumab and nivolumab are now FDA-approved for clinical use in metastatic melanoma while atezolizumab has received FDA breakthrough status for non-small cell lung cancer (NSCLC) and UC of the bladder [12]. Pembrolizumab was recently granted a priority review by the FDA for the treatment of NSCLC after progression on platinum-based chemotherapy, with a final decision pending in October 2015. There are many clinical trialsongoing currently that are testing these and many other checkpoint inhibitors. CTLA-4 is expressed exclusively on T-cells and primarily regulates the amplitude of early T-cell activation. While constitutively expressed on Foxp3 + regulatory T-cells (Treg), CTLA-4 expression is induced in activated CD8 + effector T cells, where it induces down-regulation of CD4 + T cell activity [13]. CTLA-4 counteracts the activity of the T cell co-stimulatory receptor CD28. Both compete for the same ligands on antigen presenting cells (APCs), CD80 and CD86, though CTLA-4 has a much higher affinity for both, thus MDS1-EVI1 dampening the CD28 stimulatory effect [14]. The critical role for CTLA-4 in silencing T cell activation was vividly demonstrated in the lethal systemic autoimmune sequelae observed in CTLA-4 knockout mice [15]. Indeed, targeting CTLA-4 (e.g. with ipilimumab) appears to carry the highest risks of autoimmune side effects when compared to PD-1 and PD-L1 toxicity [16, 17]. PD-1 is a cell-surface molecule that is activated by two ligands, PD-L1.