Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

Abstract

Melanoma is the most fatal skin cancer. In the early stages, it can be safely treated with surgery alone. However, since 2011, there has been an important revolution in the treatment of melanoma with new effective treatments. Targeted therapy and immunotherapy with checkpoint inhibitors have changed the history of this disease. To date, more than half of advanced melanoma patients are alive at 5 years; despite this breakthrough, approximately half of the patients still do not respond to treatment. For these reasons, new therapeutic strategies are required to expand the number of patients who can benefit from immunotherapy or combination with targeted therapy. Current research aims at preventing primary and acquired resistance, which are both responsible for treatment failure in about 50% of patients. This could increase the effectiveness of available drugs and allow for the evaluation of new combinations and new targets. The main pathways and molecules under study are the IDO inhibitor, TLR9 agonist, STING, LAG-3, TIM-3, HDAC inhibitors, pegylated IL-2 (NKTR-214), GITR, and adenosine pathway inhibitors, among others (there are currently about 3000 trials that are evaluating immunotherapeutic combinations in different tumors). Other promising strategies are cancer vaccines and oncolytic viruses. Another approach is to isolate and remove immune cells (DCs, T cells, and NK cells) from the patient’s blood or tumor infiltrates, add specific gene fragments, expand them in culture with growth factors, and re-inoculate into the same patient. TILs, TCR gene transfer, and CAR-T therapy follow this approach. In this article, we give an overview over the current status of melanoma therapies, the clinical rationale for choosing treatments, and the new immunotherapy approaches.

A rare case of pancreatic metastasis from malignant melanoma mimicking pancreatitis on 18F-FDG PET/CT

“…A similar report was described by Tma and colleagues, who detected a mass located in the pancreas head in a 71-year-old female, resulted in a metastasis from MM at histology after EUS-FNA [2]. Recently introduced IT through immune checkpoint inhibitors, directed towards specific biomarkers such as programmed death-1 (PD-1) and PD-1 ligand (PDL-1), have thoroughly changed melanoma's therapeutic landscape [3]. However, it has to be underscored that only 20-40% of patients respond to IT.…”

The Inflammatory Status of Soluble Microenvironment Influences the Capacity of Melanoma Cells to Control T-Cell Responses

“…Considering that co-inhibitory molecules have been explored to promote anticancer T-cell responses and constitute therapeutic targets in the treatment of melanoma ( 25 ), we decided to assess the transcriptional levels of TIM-3 and LAG-3 in PBMCS exposed to iSec. Interestingly, the mRNA levels of both genes were found to be significantly reduced in PBMCs exposed to iSec.…”

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

“…Immune checkpoint inhibitor therapies have successfully revolutionized the landscape of therapeutic weapons in different types of cancer, namely, lung cancer [ 265 ], skin melanoma [ 266 ], head and neck cancer [ 267 ], among others, and is being envisioned as one of the current most promising strategies to tackle cancer. Programmed cell death receptor-1 (PD-1), one of the best studied and most advanced immune checkpoint inhibition targets, is expressed in lymphocytes (T and B cells), macrophages and natural killer cells and their effector function is halted when it binds its co-ligands programmed cell death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2), which are expressed in contacting cells, including antigen-presenting cells, regulatory T-cells and neoplastic cells [ 268 , 269 ].…”