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Treatment of patients with advanced metastatic melanoma has for decades been a story of very limited success. This dramatically changed when therapy with anti-PD-1 checkpoint blocking antibodies was approved in the USA and Europe in 2014 and 2015, respectively. The therapy exploits the capacity of CD8 T cells to specifically kill tumor cells. Within the tumor microenvironment, CD8 T cell activity is blocked by suppressive signals received via PD-1, an inhibitory co-receptor and so-called checkpoint of T cell activation. PD-1 binds to its ligand PD-L1 on melanoma cells which dampens the T cell's activity. Antibodies blocking inhibitory PD-1/PD-L1 interaction release T cells from suppression. Treatment of late-stage disease melanoma patients with antibodies targeting the PD-1/PD-L1 axis, termed immune checkpoint blocking therapy (ICBT), yields clinical frequently long-lasting responses in 30-40% of cases. Despite this remarkable breakthrough, still the majority of patients resists ICBT or develops resistance after initial therapy response. Administration of anti-PD-1 antibodies in combination with antibodies targeting CTLA-4, another inhibitory immune checkpoint increased clinical responses rate up to 50% but at costs of higher treatment-related toxicities. Thus, strong efforts are now directed toward the understanding of therapy resistance, the identification of biomarkers predicting therapy response, and the development of alternative PD-1-based combination treatment to improve patient outcomes.
This article was published in the following journal.
Name: Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer
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A Phase II Trial of Neoadjuvant Treatment With PD-1 Inhibition (Nivolumab) With or Without IDO Inhibition (BMS-986205) and With or Without CTLA-4 Inhibition (Ipilimumab) in Resectable Stage III or IV Melanoma
This research study is studying different immunotherapy regimens as a possible treatment for stage III or IV resectable melanoma.
An unpigmented malignant melanoma. It is an anaplastic melanoma consisting of cells derived from melanoblasts but not forming melanin. (Dorland, 27th ed; Stedman, 25th ed)
Learned expectation that one's responses are independent of reward and, hence, do not predict or control the occurrence of rewards. Learned helplessness derives from a history, experimentally induced or naturally occurring, of having received punishment/aversive stimulation regardless of responses made. Such circumstances result in an impaired ability to learn. Used for human or animal populations. (APA, Thesaurus of Psychological Index Terms, 1994)
A serine/threonine-specific protein kinase which is encoded by the CHEK1 gene in humans. Checkpoint kinase 1 (also known as Chk1) coordinates DNA damage response and cell cycle checkpoint response. Under these conditions, activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death, to prevent damaged cells from progressing through the cell cycle.
Experimentally induced tumor that produces MELANIN in animals to provide a model for studying human MELANOMA.
An anti-CTLA-4 ANTIGEN monoclonal antibody initially indicated for the treatment of certain types of metastatic MELANOMA. Its mode of actions may include blocking of CTLA-4 mediated inhibition of CYTOTOXIC T LYMPHOCYTES, allowing for more efficient destruction of target tumor cells.
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There are three main types of skin cancer: basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Basal cell carcinoma Basal cell carcinoma, or BCC, is a cancer of the basal cells at the bottom of the epidermis. It’s very common ...
An antibody is a protein produced by the body's immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (such as bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produc...