The introduction of LAG-3 checkpoint blockade in melanoma: immunotherapy landscape beyond PD-1 and CTLA-4 inhibition

Despite major advances with immunotherapy and targeted therapy in the past decade, metastatic melanoma continues to be a deadly disease for close half of all patients. Over advancement immune profiling deeper understanding tumor microenvironment (TME) have enabled development novel approaches targeting multitude targets being investigated melanoma. However, date, checkpoint blockade has remained most successful programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors, alone or combination, yielding robust durable clinical outcome patients The highest rate responses is achieved combination PD-1 CTLA-4 inhibition, effective variety settings including brain metastases; however, it comes at expense life-threatening toxicities occurring up 60% This also established as forefront immuno-oncology (IO) drug development, search checkpoints been ongoing multiple relevant T-cell immunoglobulin mucinodomain containing-3 (TIM-3), LAG-3, V-domain suppressor activation (VISTA), immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), among others. Lymphocyte gene-3 (LAG-3), which co-inhibitory receptor on T cells that suppress their activation, revolutionized immunomodulation ‘game changing’ results from RELATIVITY-047 trial validated LAG-3 biological target third clinically checkpoint. Importantly, inhibition offered impressive efficacy modest increases toxicity over single agent inhibitor U.S. Food Drug Administration approved first-line this untreated leptomeningeal metastases rare types, such uveal melanoma, remains established. challenge elucidate specific mechanisms response resistance extend its benefits other malignancies. Ongoing trials are studying antibodies inhibitors cancers settings. low may allow further layering additional therapeutic chemotherapy, oncolytic viruses, cellular therapies, possibly cytokines,