T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

Terms of useThis work is brought to you by the University of Southern Denmark through the SDU Research Portal. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply:• You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version DIAGNOSIS AND TREATMENT OF BASAL CELL CARCINOMA: EUROPEAN CONSENSUS-BASED INTERDISCIPLINARY GUIDELINES On behalf of the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC)

Cutaneous melanoma (CM) is potentially the most dangerous form of skin tumor and causes 90% of skin cancer mortality. A unique collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO), and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on CM diagnosis and treatment, based on systematic literature reviews and the experts' experience. The diagnosis of melanoma can be made clinically and shall always be confirmed through dermatoscopy. If a melanoma is suspected, a histopathological examination is required. Sequential digital dermatoscopy and fullbody photography can be used in risk persons to detect the development of melanomas at an earlier stage. Where available, confocal reflectance microscopy can improve clinical diagnosis in special cases. Melanoma shall be classified according to the 8th version of the AJCC classification. Thin melanomas up to 0.8 mm tumor thickness does not require further imaging diagnostics. From stage IB onwards, examinations with lymph node sonography are recommended, but no further imaging examinations. From stage IIC whole-body examinations with CT or PET-CT in combination with brain MRI are recommended. From stage III and higher, mutation testing is recommended, particularly for BRAF V600 mutation. It is important to provide a structured follow-up to detect relapses and secondary primary melanomas as early as possible. There is no evidence to support the frequency and extent of examinations. A stagebased follow-up scheme is proposed, which, according to the experience of the guideline group, covers the minimum requirements; further studies may be considered. This guideline is valid until the end of 2021.

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When released into or formed in the extracellular space, adenosine acts as an autacoid via interaction with four types of G protein 1 -coupled receptors, termed A 1 -, A 2A -, A 2B -, and A 3 -adenosine receptor. These receptors are encoded by distinct genes and can be differentiated based on their affinities for adenosine analogues and methylxanthine antagonists (1, 2). In addition, the receptors can be classified based on their mechanism of signal transduction; A 1 -and A 3 -adenosine receptors interact with pertussis toxin-sensitive G proteins of the G i and G o family (3, 4, 5), whereas A 2A -and A 2B -adenosine receptors stimulate adenylyl cyclase via G s (6, 7).Adenosine is ubiquitously released by hypoxic tissues in large amounts; the nucleoside has therefore been proposed as one of the angiogenic factors that link the altered metabolism in oxygen-deprived cells to the formation of new capillaries (8).Earlier observations suggested that adenosine acts as an endothelial mitogen in vivo (9, 10). The mitogenic effect of adenosine has been verified in cultured endothelial cells derived from several vascular beds (11-13). In human endothelial cells, the proliferative response is mediated by the A 2A -adenosine receptor, an effect mimicked by stimulation of the endothelial ␤ 2 -adrenergic receptor (14). However, the mechanism by which adenosine analogues promote endothelial cell growth is not clear; there is, in particular, the apparent paradox that persistent stimulation of the signaling cascade composed of G s , adenylyl cyclase, and protein kinase A, which is downstream of A 2A -adenosine receptor, inhibits endothelial cell proliferation (14 -16). In the present work, we have therefore searched for additional effector mechanisms. We report that, in human endothelial cells, the A 2A -adenosine receptor stimulates the mitogen-activated protein kinase; this activation is independent of G s , G i , and typical protein kinase C isoforms but is associated with activation of p21 ras . EXPERIMENTAL PROCEDURESMaterials-Cell culture media were from Life Technologies, Inc., and cell culture dishes were from Greiner (Krems, Austria). [␥-32 P]ATP and [ 32 P]orthophosphate were from DuPont NEN. Cholera toxin, CPA, (Ϫ)isoproterenol, 8-Br-cAMP, collagenase (type IV), TPA, protein ASepharose, rabbit anti-rat IgG, forskolin, and epidermal growth factor (EGF) were obtained from Sigma, pertussis toxin was from Peninsula Laboratories (St. Helens, UK); bFGF, guanine nucleotides, and adenosine deaminase were from Boehringer Mannheim (FRG); XAC was from Research Biochemicals (Natick, MA), GF109203X was from Calbiochem, molecular weight standards (covering the range from 14 to 97 kDa) and reagents for SDS-polyacrylamide gel electrophoresis were from Bio-Rad. PD 098059, an inhibitor of MAP kinase kinase 1 (17), was from New England BioLabs (Beverly, MA). NECA and CGS 21680 were