αvβ3-dependent cross-presentation of matrix metalloproteinase–2 by melanoma cells gives rise to a new tumor antigen

A large array of antigens that are recognized by tumor-specific T cells has been identified and shown to be generated through various processes. We describe a new mechanism underlying T cell recognition of melanoma cells, which involves the generation of a major histocompatibility complex class I–restricted epitope after tumor-mediated uptake and processing of an extracellular protein—a process referred to as cross-presentation—which is believed to be restricted to immune cells. We show that melanoma cells cross-present, in an αvβ3-dependent manner, an antigen derived from secreted matrix metalloproteinase–2 (MMP-2) to human leukocyte antigen A*0201-restricted T cells. Because MMP-2 activity is critical for melanoma progression, the MMP-2 peptide should be cross-presented by most progressing melanomas and represents a unique antigen for vaccine therapy of these tumors

TCR Analyses of Two Vast and Shared Melanoma Antigen-Specific T Cell Repertoires: Common and Specific Features

Among Immunotherapeutic approaches for cancer treatment, the adoptive transfer of antigen specific T cells is still a relevant approach, that could have higher efficacy when further combined with immune check-point blockade. A high number of adoptive transfer trials have been performed in metastatic melanoma, due to its high immunogenic potential, either with polyclonal TIL or antigen-specific polyclonal populations. In this setting, the extensive characterization of T cell functions and receptor diversity of infused polyclonal T cells is required, notably for monitoring purposes. We developed a clinical grade procedure for the selection and amplification of polyclonal CD8 T cells, specific for two shared and widely expressed melanoma antigens: Melan-A and MELOE-1. This procedure is currently used in a clinical trial for HLA-A2 metastatic melanoma patients. In this study, we characterized the T-cell diversity (T-cell repertoire) of such T cell populations using a new RNAseq strategy. We first assessed the added-value of TCR receptor sequencing, in terms of sensitivity and specificity, by direct comparison with cytometry analysis of the T cell populations labeled with anti-Vß-specific antibodies. Results from these analyzes also confirmed specific features already reported for Melan-A and MELOE-1 specific T cell repertoires in terms of V-alpha recurrence usage, on a very high number of T cell clonotypes. Furthermore, these analyses also revealed undescribed features, such as the recurrence of a specific motif in the CDR3α region for MELOE-1 specific T cell repertoire. Finally, the analysis of a large number of T cell clonotypes originating from various patients revealed the existence of public CDR3α and ß clonotypes for Melan-A and MELOE-1 specific T cells. In conclusion, this method of high throughput TCR sequencing is a reliable and powerful approach to deeply characterize polyclonal T cell repertoires, and to reveal specific features of a given TCR repertoire, that would be useful for immune follow-up of cancer patients treated by immunotherapeutic approaches

Smart E-Skin Cancer Care in Europe During and After the COVID-19 Pandemic: A Multidisciplinary Expert Consensus

Introduction: Melanoma is the deadliest of all the skin cancers and its incidence is increasing every year in Europe. Patients with melanoma often present late to the specialist and treatment is delayed for many reasons (delay in patient consultation, misdiagnosis by general practitioners, and/or limited access to dermatologists). Beyond this, there are significant inequalities in skin cancer between population groups within the same country and between countries across Europe. The emergence of the COVID-19 pandemic only aggravated these health deficiencies. Objectives: The aim was to create an expert opinion about the challenges in skin cancer management in Europe during the post COVID-19 acute pandemic and to identify and discuss the implementation of new technologies (including e-health and artificial intelligence defined as "Smart Skin Cancer Care") to overcome them. Methods: For this purpose, an ad-hoc questionnaire with items addressing topics of skin cancer care was developed, answered independently and discussed by a multidisciplinary European panel of experts comprising dermatologists, dermato-oncologists, patient advocacy representatives, digital health technology experts, and health technology assessment experts. Results: After all panel of experts discussions, a multidisciplinary expert opinion was created. Conclusions: As a conclusion, the access to dermatologists is difficult and will be aggravated in the near future. This fact, together with important differences in Skin Cancer Care in Europe, suggest the need of a new approach to skin health, prevention and disease management paradigm (focused on integration of new technologies) to minimize the impact of skin cancer and to ensure optimal quality and equity

A Novel Actinic Keratosis Field Assessment Scale For Grading Actinic Keratosis Disease Severity

Actinic keratosis (AK) lesions are surrounded by field cancerization (areas of subclinical, non-visible sun damage). Existing AK grading tools rely on AK counts, which are not reproducible. An Actinic Keratosis Field Assessment Scale (AK-FAS) for grading the severity of AK/field was developed. Standardized photographs of patients representing the full range of AK severity were collected. Six investigators independently rated each photograph according to 3 criteria: AK area (total skin area affected by AK lesions), hyperkeratosis and sun damage. Inter-rater reproducibility was good for all 3 criteria. Validation of the AK-FAS showed good reproducibility for AK area and hyperkeratosis, even for dermatologists untrained on use of the scale. In conclusion, the AK-FAS is objective, easy to use and implement, and reproducible. It incorporates assessment of the entire field affected by AK instead of relying on lesion counts. Use of the AK-FAS may standardize AK diagnosis, making it relevant to routine clinical practice

First-line, fixed-duration nivolumab plus ipilimumab followed by nivolumab in clinically diverse patient populations with unresectable stage III or IV melanoma: Checkmate 401

PURPOSE: To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS: Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤ 24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS: In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months\u27 median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION: Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

First-Line, Fixed-Duration Nivolumab Plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

PURPOSE To address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma. METHODS Treatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for ≤24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype. RESULTS In total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup. CONCLUSION Nivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

Pimasertib Versus Dacarbazine in Patients With UnresectableNRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2 ; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42–0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00–4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61–1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

Rôle de l'hérédité dans l'acné

L'acné est une dermatose considérée comme l'une des plus fréquemment rencontrées en pratique médicale courante atteignant près de 80% des adolescents.Une meilleure connaissance de la physiopathologie et de l'anatomoclinique a permis une approche thérapeutique mieux adaptée. Cependant, un certain nombre d'inconnues persiste sur les facteurs susceptibles d'intervenir dans le développement, le déclenchement ou l'aggravation de l'acné.Afin de mieux connaître le rôle de l'un de ces facteurs, le facteur héréditaire, nous avons mené une étude parmi des patients acnéiques avec et sans antécédents familiaux d'acné comparant divers critères tels que la précocité, la sévérité de l'acné et la réponse aux thérapeutiques anti-acnéiques. Nous avons également cherché à préciser l'influence de l'antécédent familial d'acné suivant qu'il provient du père, de la mère ou des deux parents.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Mise en évidence des effets anti-inflammatoires du gluconate de lithium dans la dermatite séborrhéique

Le gluconate de lithium (Li) topique est un traitement efficace de la dermite séborrhéique (DS). Cependant, son mécanisme d action reste mal compris. Le but de notre travail était d étudier in vitro, l effet modulateur du Li sur la prolifération ,la différenciation kératinocytaire, l expression et la sécrétion de cytokines pro- ou anti-inflammatoires et sur l expression des Toll-like recepteurs (TLR) 2 et 4. Pour cela, des kératinocytes cultivés en monocouche et des explants cutanés étaient stimulés ou non avec du LPS ou du zymosan afin d induire une inflammation, puis étaient incubés avec le Li à 1,6 ; 3 ou 5mM, ou avec un milieu contrôle. L expression de Ki67, de la kératine 10, de la filaggrine, des cytokines TNFalpha, IL6, IL10, TGFb1 et des récepteurs TLR2 et 4 était déterminée par immunohistochimie et la sécrétion des cytokines quantifiée par une méthode ELISA. Concernant la prolifération kératinocytaire, le nombre de cellules exprimant le Ki67 diminuait en présence de Li, de manière dose dépendante. Mais cette modulation n était significative que lors de stimulation préalable des kératinocytes par LPS. Concernant les marqueurs de différenciation, le Li à la concentration de 5mM, était associé à une augmentation de l expression de K10 par les kératinocytes en monocouche et à une extension de l expression de la filaggrine au niveau des couches spineuses des explants. Concernant les cytokines, il était mis en évidence une augmentation significative de la sécrétion de TNFalpha avec 1.6 mM de Li et une augmentation de l expression et de la sécrétion d IL10 par les kératinocytes avec 5mM de Li. Le Li à 5mM diminuait également significativement l expression de TLR2 et TLR4 par les kératinocytes différenciés. L effet immunomodulateur du Li apparaît donc dose-dépendant. Ceci expliquerait l effet paradoxal du Li selon la voie d utilisation : exacerbation de la DS lors d administration systémique (taux faible de Li dans la peau), amélioration de la DS sous traitement topique induisant des taux plus élevés de Li dans l épiderme. Notre étude met en évidence deux mécanismes anti-inflammatoires des sels de lithium : induction de la secrétion d IL10 par les kératinocytes et inhibition de l expression de TLR2 et TLR4.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Place de la biochimiothérapie (association cytokine et chimiothérapie) dans le mélanome métastatique (à partir d'une étude rétrospective)

Le pronostic du mélanome métastatique reste à ce jour très réservé en raison de l'efficacité modérée des traitements proposés. Afin d'améliorer la survie des patients, de nombreux essais ont été développés pour étudier la biochimiothérapie (association chimiothérapie-immunothérapie). Dans cette étude rétrospective concernant 59 patients, nous avons tenté de définir les intérêts et les limites de ces associations. Dans notre étude comme dans la littérature, le bénéfice de la biochimiothérapie versus une chimiothérapie seule semble réel pour certains sujets mais non significatif pour l'ensemble des patients. L'émergence des nouvelles technologies nous permettra probablement de mieux identifier les facteurs de réponse relatifs à la tumeur et au patient, et d'utiliser ce traitement (dont la toxicité n'est pas négligeable) dans une population mieux ciblée.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF