Future perspectives in melanoma research “Melanoma Bridge”, Napoli, November 30th–3rd December 2016

Abstract

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.

Gene expression analysis in formalin fixed paraffin embedded melanomas is associated with density of corresponding immune cells in those tissues

“…Several gene expression profiles have been reported to predict clinical responses to systemic immunotherapy 1 – 5 and to be prognostic for patients with a range of cancers, including melanoma 6 – 9 . A more traditional approach for defining immunologic features of the TME has been to quantify numbers of selected intratumoral immune cells within the TME which has also been found to predict responses to certain immunotherapies or overall prognosis from melanoma 6 , 7 , 10 – 12 and other cancers 13 , 14 . Pathologists can report immune cell density on formalin-fixed paraffin-embedded (FFPE) tissue using hematoxylin and eosin (H&E) stains or immunohistochemistry (IHC), but these modalities are cumbersome and costly to integrate into routine clinical practice as quantitative assays.…”

Three-gene prognostic biomarkers for seminoma identified by weighted gene co-expression network analysis

“…One study investigating biomarkers in breast cancer brain metastasis via integrated genomic and epigenomic analysis showed that hypermethylation and downregulation of ITGAM were associated with defects in cell migration and adhesion [ 35 ]. One meeting report in 2016 described that ITGAM protein positive tumor associated macrophages were associated with tumor angiogenesis promotion and immunosuppression [ 38 ].…”

Associations of immune cell homing gene signatures and infiltrates of lymphocyte subsets in human melanomas: discordance with CD163+ myeloid cell infiltrates

“…The density, location, and function of immune cells in the tumor microenvironment (TME), especially CD8 + T cells, are prognostic in melanoma [ 1 – 6 ] and other cancers [ 7 – 9 ], and can predict patient responses to immunomodulating therapies [ 10 – 13 ]. Others and we have also shown that the density of intratumoral B cells is associated with prolonged survival in melanoma [ 5 , 14 – 19 ].…”