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.

Keywords: adoptive cell therapy; anti-LAG-3; bempegaldesleukin; cutaneous melanoma; immunotherapy; lenvatinib; metastatic melanoma; novel targets; targeted therapy; vaccine.

Figure 1

LAG3/MHC Class II Signaling Pathway. (1) LAG-3 is commonly expressed on regulatory T cells (Treg), effector T cells, and NK cells. Its main ligand is MHC class II, which is found upregulated on some tumor cells, tumor-infiltrating macrophages, and dendritic cells (DCs). LAG-3-MHC II interaction promotes inhibition of the responses of effector T cells and promotes the suppressive activity of Treg. (2) Double blocking of LAG3 and PD1 in synergy using antagonist antibodies against LAG3 in combination with PD-1/PD-L1 blockade, represents a novel strategy in oncology. Indeed, co-blocking LAG-3 and PD-1 enhances T-cell effectors and NK cells proliferation, promotes the release of pro-inflammatory cytokine, and inhibits Treg cells [21].

Figure 2

Model for GITR modulation of antitumor immunity. (1) GITR ligand (GITRL) is mainly expressed on tumor cells or antigen presenting cells (APCs). High levels of GITR are normally expressed on regulatory T cells (Treg). In contrast, on effector T cells, GITR expression is upregulated following activation by TCR-MCH interaction. (2) GITR engagement on Treg cells promotes Treg cells activation and proliferation and inhibits proliferation of effector T and NK cells. (3) Conversely, GITR-GITRL interaction on effector T cells promotes antitumor activity of T cells by enhancing CD4+ and CD8+ T-cell proliferation and downregulates the immunosuppressive activity of Tregs. Activation of effector T cells can also be stimulated using agonists anti-GITR, such as BMS-986156 or TRX518.

Figure 3

TIGIT in cancer immunotherapy (1) TIGIT is expressed on effector T and NK cells. TIGIT binds two ligands, CD155 and CD112, that are expressed on tumor cells and dendritic cells (DCs). (2) TIGIT-CD155 interaction in DCs promotes the release of anti-inflammatory cytokines such as IL-10, which impairs T effector and NK cells activation. (3) Interaction between TIGT-CD155/CD112 in regulatory T cells (Treg) facilitates suppression of antitumor immune response by releasing cytokines into the tumor microenvironment, such as IL-10 and TGF-β, which have an inhibiting effect on T effector and NK cells. (4) Blocking TIGIT with monoclonal antibodies (mAbs), alone or in combination with anti-PD1, can restore T effectors and NK cells activity in cancer patients.