Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM.

BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses

A subset of dendritic cells as a major and constitutive source of IL-22BP

Poster presentationInternational audienc

Actinic Keratosis, a Chronic, Progressive Disease: Understanding Clinical Gaps to Optimise Patient Management

Actinic keratosis (AK) is a chronic, progressive disease of the skin that has undergone long-term sun exposure. The affected areas contain visible and subclinical nonvisible sun damage resulting in epidermal keratinocyte dysplasia, known by many as ‘field cancerisation’ (1), which is prone to AKs and sun-related skin cancer (2). Thus, visible AKs are clinical biomarkers for a photo-damaged field with subclinical damage associated with the unpredictable risk of progression to invasive squamous cell carcinoma (iSCC) (3). The aim of this multiexpert opinion article is to provide a discussion succinctly highlighting the clinical gaps for optimal management of AK: the lack of a universal definition and the need for a standardised grade assessment of AK/field cancerisation that also takes into account individual risk

Cutibacterium acnes (Propionibacterium acnes) and acne vulgaris: a brief look at the latest updates

While the commensal bacterium Propionibacterium acnes (P. acnes) is involved in the maintenance of a healthy skin, it can also act as an opportunistic pathogen in acne vulgaris. The latest findings on P. acnes shed light on the critical role of a tight equilibrium between members of its phylotypes and within the skin microbiota in the development of this skin disease. Indeed, contrary to what was previously thought, proliferation of P. acnes is not the trigger of acne as patients with acne do not harbour more P. acnes in follicles than normal individuals. Instead, the loss of the skin microbial diversity together with the activation of the innate immunity might lead to this chronic inflammatory condition. This review provides results of the most recent biochemical and genomic investigations that led to the new taxonomic classification of P. acnes renamed Cutibacterium acnes (C. acnes), and to the better characterisation of its phylogenetic cluster groups. Moreover, the latest data on the role of C. acnes and its different phylotypes in acne are presented, providing an overview of the factors that could participate in the virulence and in the antimicrobial resistance of acne-associated strains. Overall, this emerging key information offers new perspectives in the treatment of acne, with future innovative strategies focusing on C. acnes biofilms and/or on its acne-associated phylotypes

Double Positive CD4CD8 αβ T Cells: A New Tumor-Reactive Population in Human Melanomas

BACKGROUND: Double positive (DP) CD4CD8 Talphabeta cells have been reported in normal individuals as well as in different pathological conditions including inflammatory diseases, viral infections and cancer, but their function remains to be elucidated. We recently reported the increased frequency of DP Talphabeta cells in human breast pleural effusions. This manuscript addresses the question of the existence and above all the role of this non-conventional DP sub-population among tumor associated lymphocytes in melanomas. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed the intratumoral cell infiltrate in solid metastasis (n = 6) and tumor invaded lymph nodes (n = 26) samples from melanomas patients by multiparametric cytometry. Here we documented for the first time significant increased frequency of DP T cells in about 60% of melanoma tumors compared to blood samples. Interestingly, a high proportion of these cells produced TNF-alpha in response to autologous melanoma cell lines. Besides, they are characterized by a unique cytokine profile corresponding to higher secretion of IL-13, IL-4 and IL-5 than simple positive T cells. In deep analysis, we derived a representative tumor-reactive DP T cell clone from a melanoma patient's invaded lymph node. This clone was restricted by HLA-A*2402 and recognized both autologous and allogeneic tumor cells of various origins as well as normal cells, suggesting that the target antigen was a ubiquitous self antigen. However, this DP T cell clone failed to kill HLA-A*2402 EBV-transformed B cells, probably due to the constitutive expression of immunoproteasome by these cells. CONCLUSIONS/SIGNIFICANCE: In conclusion, we can postulate that, according to their broad tumor reactivity and to their original cytokine profile, the tumor associated DP T cells could participate in immune responses to tumors in vivo. Therefore, the presence of these cells and their role will be crucial to address in cancer patients, especially in the context of immunotherapies

Value of large scale expansion of tumor infiltrating lymphocytes in a compartmentalised gas-permeable bag: interests for adoptive immunotherapy

<p>Abstract</p> <p>Background</p> <p>Adoptive cell therapy (ACT) has emerged as an effective treatment for patients with metastatic melanoma. However, there are several logistical and safety concerns associated with large-scale <it>ex vivo </it>expansion of tumour-specific T lymphocytes for widespread availability of ACT for cancer patients. To address these problems we developed a specific compartmentalised bag allowing efficient expansion of tumour-specific T lymphocytes in an easy handling, closed system.</p> <p>Methods</p> <p>Starting from lymph nodes from eight melanoma patients, we performed a side-by-side comparison of Tumour-Infiltrating Lymphocytes (TIL) produced after expansion in the compartmentalised bag versus TIL produced using the standard process in plates. Proliferation yield, viability, phenotype and IFNγ secretion were comparatively studied.</p> <p>Results</p> <p>We found no differences in proliferation yield and cell viability between both TIL production systems. Moreover, each of the cell products complied with our defined release criteria before being administered to the patient. The phenotype analysis indicated that the compartmentalised bag favours the expansion of CD8+ cells. Finally, we found that TIL stimulated in bags were enriched in reactive CD8+ T cells when co-cultured with the autologous melanoma cell line.</p> <p>Conclusions</p> <p>The stimulation of TIL with feeder cells in the specifically designed compartmentalised bag can advantageously replace the conventional protocol using plates. In particular, the higher expansion rate of reactive CD8+ T cells could have a significant impact for ACT.</p

Characterisation of Cutibacterium acnes phylotypes in acne and in vivo exploratory evaluation of Myrtacine®

OBJECTIVE : Our main objective was to compare Cutibacterium acnes (C. acnes) skin colonisation in patients with mild to moderate acne versus healthy controls and secondly, to evaluate a Myrtacine® -based cream on C. acnes total population and antibioresistant Cutibacteria in patients with acne. METHODS:In 60 acne patients (Global Acne Severity Scale, GEA grades 2-3), of mean age 20 [15-30] years and in 24 age- and sex- matched healthy controls, forehead strips samplings were performed for microbiological analysis of comedones by colony forming unit (CFU) counts of global C. acnes and erythromycin (EryR) or clindamycin-resistant (ClnR) populations of Cutibacterium and determination of phylotypes by MALTI-TOF. Clinical evaluations of acne patients (GEA, lesion count, porphyrin fluorescence) were performed at baseline and after 56 days of twice-daily application of a Myrtacine® -based cream. RESULTS : We first showed (i) high and similar levels of C. acnes colonisation in superficial pilosebaceous follicles and detection of EryR and ClnR strains in both acne and control groups; (ii) different repartition of phylotypes in acne patients versus healthy control, with a predominance of phylotype IA in acne patients and a link between phylotype IA and erythromycin resistance. Besides, after treatment with the Myrtacine® -based cream in acne patients, there was no change in C. acnes total load, but a significant decrease of EryR Cutibacteria, reduced porphyrin production by C. acnes, a decrease in acne severity (GEA), associated with reduced retentional and inflammatory lesions. CONCLUSION : Cutibacterium acnes colonisation was not significantly different in acne versus control groups. Phylotype IA was predominant in acne patient and in EryR C. acnes. A Myrtacine® -based cream significantly reduced the level of EryR Cutibacteria in vivo and improved acne lesions

Identifying gaps and providing recommendations to address shortcomings in the investigation of acne sequelae by the Personalising Acne: Consensus of Experts panel

Background: The physical sequelae of acne include erythema, hyperpigmentation, and scarring, which are highly burdensome for patients. Early, effective treatment can potentially limit and prevent sequelae development, but there is a need for guidance for and evidence of prevention-oriented management to improve patient outcomes. Objective: To identify unmet needs of acne sequelae and generate expert recommendations to address gaps in clinical guidance. Methods: The Personalizing Acne: Consensus of Experts panel of 13 dermatologists used a modified Delphi approach to achieve a consensus on the clinical aspects of acne sequelae. A consensus was defined as ≥75% of the dermatologists voting agree or strongly agree. All voting was electronic and blinded. Results: The panel identified gaps in current guidance and made recommendations related to acne sequelae. These included identification and classification of sequelae, pertinent points to consider for patient consultations, and management aimed at reducing the development of sequelae. Limitations: The recommendations are based on expert opinion and made in the absence of high-quality evidence. Conclusions: The identified gaps should help inform future research and guideline development for acne sequelae. The consensus-based recommendations should also support the process of consultations throughout the patient journey, helping to reduce the development and burden of acne sequelae through improved risk factor recognition, early discussion, and appropriate management