Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Abstract

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

“…Recent works have highlighted the potential role of HDACs in melanoma progression 7,41,42 . The epigenetic control of MITF/AXL status has been reported in several types of cancer.…”

Sequencing of Targeted Treatment and Immunotherapy in Advanced BRAF-Mutant Melanoma

“…Even in the current era of rapid advances, patients with adverse disease biology and poor clinical symptomatology have an unfavorable prognosis regardless of treatment approach, and this remains an area of unmet need. 5 Some patients with critical disease may prioritize the high chance of short-term symptom control and better quality of life from TT over the uncertain promise of longer survival with combination ICI. Adopting the sandwich tactic may risk discontinuation of an effective treatment for speculative benefit and introduce serious toxicity risk that could preclude/delay switching back to TT when needed, compromising well-being when end of life is close.…”

Tumor-Infiltrating Lymphocyte Therapy in Melanoma: Facts to the Future

“…Intrinsic and acquired resistance to front-line ICIs is common and driven by multiple factors (13). Resistance, with a high likelihood of recurrent disease in patients receiving adjuvant ICIs, further emphasizes the need for effective treatments in this ICI-refractory population (14). A variety of immune-activating adoptive cell therapy approaches are being tested in the hope of overcoming these resistance mechanisms (15,16).…”