Increased tumor burden, it being in FDG-uptake (SUV) or a number of FDG-avid lesions, is usually classified as progression according to the PERCIST and EORTC criteria, both developed for evaluation during chemotherapy [39]. this review will primarily focus on patients with malignant melanoma. strong class=”kwd-title” Keywords: immune checkpoint inhibitor therapy, PET/CT, radiotracer, response evaluation/treatment monitoring 1. Introduction Evasion of attack by the immune system is one of the hallmarks of cancer [1]. Based on the amount of mutations being accumulated by cancer cells, immune cells should register cancer cells as being foreign. One reason why this fails is because of the development of tolerance. Several mechanisms guide CEP-1347 the development of tolerance, including immune checkpoint pathways, which downregulates immune function to prevent immune cells from being self-reactive. Blocking these immune checkpoints stimulates an autoimmune response, but also help immune cells recognizing foreign cells such as cancer. Drugs that inhibit immune checkpoints CEP-1347 have shown clinical efficacy in several different types of cancer, e.g., melanoma, non-small cell lung cancer (NSCLC), renal and urothelial cancer, Hodgkins lymphoma and head- and neck cancer [2,3,4,5,6,7]. Encouraging results have been demonstrated especially in advanced melanoma for which the previous therapeutic options have been limited, as well as in metastatic NSCLC, currently replacing traditional platin-based chemotherapy as first-line therapy in selected patients [8,9]. The effect of immune checkpoint inhibitor therapy (ICT) on cancer cells is mediated thru activation of an immune response against the cancer cells. This indirect, immune-mediated effect has given rise Timp1 to new challenges concerning response evaluation as response patterns to ICT differ from those observed with conventional anti-cancer therapy. The aim of this article is to provide an overview of the challenges and possibilities for molecular imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), in the evaluation of patients treated with ICT. In order to put the use of different imaging modalities into the right perspective, this review starts with a brief introduction to ICT and examples of current use in patients with malignant melanoma and NSCLC. 2. Immune Checkpoint Therapy The current ICT is based on regulation of two important immune checkpoint pathways: one involving programmed cell death protein CEP-1347 (PD-1/PD-L1) and one involving the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Programmed cell death protein 1 (PD-1), is a cell surface receptor that is expressed on T cells, B cells, natural killer T cells, activated monocytes, and dendritic cells [10]. T-cells require two signals to become activated. First, CEP-1347 a signal triggered by the interaction between antigen-major histocompatibility complex (MHC) and the T cell receptor, and second a co-stimulatory signal provided by antigen-presenting cells (APCs). T-cell activation causes T cell clonal expansion, cytokine secretion and the effector function of the T cell. Binding of PD-1 to its ligand PD-L1 inhibits the co-stimulatory signal, causing a decrease in the production of cytokines and cell survival proteins, ultimately downregulating the activity of self-reactive T-cells. PD-L1 is expressed by normal immune cells as well as by many different tumor types, allowing the tumor cells to evade the immune system. The anti-PD-1 antibodies pembrolizumab and nivolumab have shown promising results in patients with metastatic melanoma not harboring the mutation in the B-Raf proto-oncogene (BRAF-mutation) with improved survival rates when compared to the anti CTLA-4 antibody ipilimumab and chemotherapy [11,12,13]. Response has been proved durable with two-year survival rates of 43% [14]. Pembrolizumab has also been shown to be an effective treatment option in advanced NSCLC, with an overall survival of 17.3 months, compared to 8.2 months with docetaxel [3]. Another important immune checkpoint involves CTLA-4. Structurally related to the CD28 receptor, it is primarily expressed on the surface of T cells. CD28 mediates the co-stimulatory signal from APCs required for activation of T cell effector function, interacting with B7-1 and B7-2 on APCs. This effect is caused by CTLA-4 ligating with B7-1 and.