ReviewThe new paradigm of systemic therapies for metastatic melanoma
Section snippets
Immune checkpoints and their inhibition
A melanoma-specific immune response is generated when melanoma antigen on the major histocompatibility complexes of antigen-presenting cells (APCs) is presented to the T-cell receptors of T cells. The antigen-primed T cell becomes activated by engagement of its CD28 molecule with the costimulatory molecules CD80 and CD86 present on APCs (Fig 2). The resulting tight synapse between the T cell and APC leads to proliferation and survival of T cells that help eliminate tumor cells.1 The CTLA-4
Adverse events secondary to immune checkpoint inhibition
The common side effects are nonspecific and include fatigue, diarrhea, rash, and nausea. Immune-related adverse events (irAEs) have been commonly seen and involve a number of organ systems, including the gastrointestinal tract (colitis, hepatitis), skin (dermatitis), lung (pneumonitis), endocrine glands (hypophysitis, thyroid dysfunction), nervous system, and eyes (Table I).3, 4, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 Dermatologic complications
Combined immune checkpoint inhibition: principle
Knowledge that blocking either of the 2 T-cell inhibitory checkpoints by monoclonal antibodies improved survival in MM patients and that these checkpoints are nonredundant led to the hypothesis that further improvement in survival might be achieved by combined blockade. Validated in preclinical studies, the first phase 1 study combined (concurrently or sequentially) ipilimumab and nivolumab treatments in unresectable stage III or IV melanoma. The results confirmed improved outcomes following
Targeted therapies
Genetic components of multiple cellular signaling pathways critical to maintaining cellular homeostasis by controlling key cellular functions of growth, proliferation, and cell death by apoptosis have been discovered. Mutations of genes encoding proteins of such pathways foster carcinogenesis by conferring uncontrolled cellular signaling for growth and proliferation. Targeted therapy involves control of tumor growth with small molecules designed to block the aberrant proteins of these signaling
BRAF inhibitors in combination with MEK inhibitors
Though BRAF inhibitors have high disease control rates, treatment failures following BRAF inhibitor monotherapy are common, with most patients developing tumor progression within 6-7 months. The tumor developing resistance to the BRAF inhibitor therapy is the main cause of treatment failure and is multifactorial.21, 54 Recent data shows that approximately two thirds of cases are caused by reactivation of oncogenic signaling via the MAPK pathway and the remainder by an MAPK-independent pathway.63
Treatment decision of a patient diagnosed with unresectable stage III or IV melanoma
The treatment options for patients with unresectable stage III or stage IV melanoma are expanding (Fig 4). A number of patient specific and disease factors are required to determine the best treatment option. These factors include treatment naïve status, previous use of immune therapy in the adjuvant setting, sites of metastasis, rate of tumor growth, tumor bulk, comorbidities including autoimmune diseases and their severities, performance status, age, serum LDH levels, and tumor PDL1 status.
Conclusion
Immune-based treatments and targeted therapies for MM have yielded promising results. Challenges still exist due to the toxicities that might limit treatment options in subsets of patients. While durable remissions are more likely with immune-based treatments, combined BRAF and MEK blockade can delay development of resistance and improve treatment outcomes.
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2022, Journal of the American Academy of DermatologyCitation Excerpt :CTLA-4 is expressed on the surface of activated regulatory T cells, which normally function to downregulate the T-cell immune response.5,6 Ipilimumab is a monoclonal antibody directed against CTLA-4, thereby promoting T-cell response and tumor lysis (Fig 2).2,4,6 Nivolumab is a monoclonal antibody against PD-1.
Galactofucoidans from Sargassum fusiforme and their antagonistic effects against the proliferation-inhibition of RAW264.7 macrophage induced by culture supernatants of melanoma cells
2021, Carbohydrate Polymer Technologies and ApplicationsCitation Excerpt :In the past few decades, the US Food and Drug Administration has approved several drugs and treatments for melanoma, such as dacarbazine, interferon α-2b, interleukin-2, and dabrafenib. However, these treatments have limited effectiveness (Domingues et al., 2018; Lui et al., 2007; Volpe, Klufas, Hegde, & Grant-Kels, 2017). As our understanding of the molecular pathogenesis of melanoma and tumor immunology has improved, the treatment of melanoma has recently undergone a revolution (Gershenwald et al., 2017).
Liquid biopsy-based analysis by ddPCR and CAPP-Seq in melanoma patients
2021, Journal of Dermatological ScienceCitation Excerpt :As melanoma patients harbor BRAF mutations that activate the RAF-MEK-ERK pathway, BRAF V600E/K is considered a therapeutic target. Although two therapies (vemurafenib and dabrafenib) targeting BRAF V600E/K are available, their treatment results are not consistently satisfactory, even in combination with downstream kinase MEK1/2 inhibitors (trametinib and cobimetinib) [24]. Most melanoma patients acquire resistance to these treatments after several months [25], thereby necessitating a novel target for melanoma treatment.
BCKDHA contributes to melanoma progression by promoting the expressions of lipogenic enzymes FASN and ACLY
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Dr Volpe and Mr Klufas contributed to this work equally.
Drs Hegde and Grant-Kels contributed to this work equally.
Funding sources: Supported by Jane and Richard Lublin.
Reprints not available from the authors.
Conflicts of interest: None declared.