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The fourth "Melanoma Bridge Meeting" took place in Naples, December 5 to 8th, 2013. The four topics discussed at this meeting were: Diagnosis and New Procedures, Molecular Advances and Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers.

Summary: Immune‐related toxicities, otherwise known as immune‐related adverse events (irAEs), occur in a substantial fraction of cancer patients treated with immune checkpoint inhibitors (ICIs). Ranging from asymptomatic to life‐threatening, ICI‐induced irAEs can result in hospital admission, high‐dose corticosteroid treatment, ICI discontinuation, and in some cases, death. A deeper understanding of the factors underpinning severe irAE development will be essential for improved irAE prediction and prevention, toward maximizing the benefits and safety profiles of ICIs. In recent work, we applied mass cytometry, single‐cell RNA sequencing, single‐cell V(D)J sequencing, bulk RNA sequencing, and bulk T‐cell receptor (TCR) sequencing to identify pretreatment determinants of severe irAE development in patients with advanced melanoma. Across 71 patients separated into three cohorts, we found that two baseline features in circulation—elevated activated CD4 effector memory T‐cell abundance and TCR diversity—are associated with severe irAE development, independent of the affected organ system within 3 months of ICI treatment initiation. Here, we provide an extended perspective on this work, synthesize and discuss related literature, and summarize practical considerations for clinical translation. Collectively, these findings lay a foundation for data‐driven and mechanistic insights into irAE development, with the potential to reduce ICI morbidity and mortality in the future. [ABSTRACT FROM AUTHOR]

Major advances have been made in the treatment of cancer with targeted therapy and immunotherapy; several FDA-approved agents with associated improvement of 1-year survival rates became available for stage IV melanoma patients. Before 2010, the 1-year survival were quite low, at 30%; in 2011, the rise to nearly 50% in the setting of treatment with Ipilimumab, and rise to 70% with BRAF inhibitor monotherapy in 2013 was observed. Even more impressive are 1-year survival rates considering combination strategies with both targeted therapy and immunotherapy, now exceeding 80%. Can we improve response rates even further, and bring these therapies to more patients? In fact, despite these advances, responses are heterogeneous and are not always durable. There is a critical need to better understand who will benefit from therapy, as well as proper timing, sequence and combination of different therapeutic agents. How can we better understand responses to therapy and optimize treatment regimens? The key to better understanding therapy and to optimizing responses is with insights gained from responses to targeted therapy and immunotherapy through translational research in human samples. Combination therapies including chemotherapy, radiotherapy, targeted therapy, electrochemotherapy with immunotherapy agents such as Immune Checkpoint Blockers are under investigation but there is much room for improvement. Adoptive T cell therapy including tumor infiltrating lymphocytes and chimeric antigen receptor modified T cells therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Tumor infiltrating lymphocytes therapy is also efficacious in metastatic melanoma and outcome enhancement seem likely by improved homing capacity of chemokine receptor transduced T cells. Understanding the mechanisms behind the development of acquired resistance and tests for biomarkers for treatment decisions are also under study and will offer new opportunities for more efficient combination therapies. Knowledge of immunologic features of the tumor microenvironment associated with response and resistance will improve the identification of patients who will derive the most benefit from monotherapy and might reveal additional immunologic determinants that could be targeted in combination with checkpoint blockade. The future of advanced melanoma needs to involve education and trials, biobanks with a focus on primary tumors, bioinformatics and empowerment of patients and clinicians. [ABSTRACT FROM AUTHOR]

RAC1 is a GTPase member of the RAS superfamily, and RAC1P29S was recently identified as the third most common recurrent mutation in melanomas, affecting 4-7% of the patients. This is an oncogenic mutation, because the mutant protein remains mostly in its active GTP-bound form, and its ectopic expression increases the rate of normal melanocytes proliferation and migration. There is limited information regarding the functional role of RAC1P29S as a "driver" in human melanogenesis and as a cause for drug resistance. This commentary describes the latest data and provides evidence that supports the notion that RAC1 is activated even in melanoma cells that do not carry the mutation rendering it a good target for therapy. On the other hand, its role in conferring resistance to BRAF or MEK inhibitors is still in question. [ABSTRACT FROM AUTHOR]

Despite the remarkable success of anti-cancer immunotherapy, its effectiveness remains confined to a subset of patients—emphasizing the importance of predictive biomarkers in clinical decision-making and further mechanistic understanding of treatment response. Current biomarkers, however, lack the power required to accurately stratify patients. Here, we identify interferon-stimulated, Ly6Ehi neutrophils as a blood-borne biomarker of anti-PD1 response in mice at baseline. Ly6Ehi neutrophils are induced by tumor-intrinsic activation of the STING (stimulator of interferon genes) signaling pathway and possess the ability to directly sensitize otherwise non-responsive tumors to anti-PD1 therapy, in part through IL12b-dependent activation of cytotoxic T cells. By translating our pre-clinical findings to a cohort of patients with non-small cell lung cancer and melanoma (n = 109), and to public data (n = 1440), we demonstrate the ability of Ly6Ehi neutrophils to predict immunotherapy response in humans with high accuracy (average AUC ≈ 0.9). Overall, our study identifies a functionally active biomarker for use in both mice and humans. [Display omitted] • Ly6Ehi neutrophils are interferon-stimulated cells present in both mouse and human • Ly6Ehi neutrophils accurately predict immunotherapy outcomes in different cancer types • Activation of the STING pathway in tumors accounts for Ly6Ehi neutrophil enrichment • Ly6Ehi neutrophils sensitize otherwise resistant tumors to immunotherapy in mice A lack of reliable, highly predictive biomarkers remains a major obstacle in immuno-oncology. In this study, Benguigui et al. discover a promising new biomarker: interferon-stimulated, Ly6Ehi neutrophils—whose frequency in the blood of both mice and patients strongly correlates with immunotherapy outcomes across cancer types. [ABSTRACT FROM AUTHOR]