Antibody therapies for melanoma: new and emerging opportunities to activate immunity (Review)

Abstract

The interface between malignant melanoma and patient immunity has long been recognised and efforts to treat this most lethal form of skin cancer by activating immune responses with cytokine, vaccine and also antibody immunotherapies have demonstrated promise in limited subsets of patients. In the present study, we discuss different antibody immunotherapy approaches evaluated in the context of melanoma, each designed to act on distinct targets and to employ different mechanisms to restrict tumour growth and spread. Monoclonal antibodies recognising melanoma-associated antigens such as CSPG4/MCSP and targeting elements of tumour-associated vasculature (VEGF) have constituted long-standing translational approaches aimed at reducing melanoma growth and metastasis. Recent insights into mechanisms of immune regulation and tumour-immune cell interactions have helped to identify checkpoint molecules on immune (CTLA4, PD-1) and tumour (PD-L1) cells as promising therapeutic targets. Checkpoint blockade with antibodies to activate immune responses and perhaps to counteract melanoma-associated immunomodulatory mechanisms led to the first clinical breakthrough in the form of an anti-CTLA4 monoclonal antibody. Novel modalities to target key mechanisms of immune suppression and to redirect potent effector cell subsets against tumours are expected to improve clinical outcomes and to provide previously unexplored avenues for therapeutic interventions.

Figure 1

Possible mechanisms of action employed by monoclonal antibodies. (A) Direct effects by specific recognition of cell surface target antigens, triggering possible downstream signalling events that lead to target cell death. (B) Antibody-dependent cell-mediated cytotoxicity (ADCC) is based on antigen target-reactive antibodies coating tumour cells recognised by Fc receptors expressed on immune cells such as NK cells, macrophages and neutrophils; these lead to effector cell activation and tumour cell death (left). Antibody-coated tumour cells can also engage Fc receptors present on phagocytes leading to antibody-dependent cell-mediated phagocytosis (ADCP) (right) of the target cell. (C) Targeting VEGF prevents its association with its cell surface receptors (VEGFR1, VEGFR2) preventing downstream signals that lead to formation of tumour-associated vasculature. (D) Targeting the checkpoint molecule CTLA4; CTLA4 binds to B7 on antigen presenting cells (APC) and interferes with CD28-B7 complex co-stimulatory signals needed for MHC-antigen-TCR antigen presentation, thus inhibiting T cell activation. Antibodies such as ipilimumab block binding of CTLA4 to B7 on the surface of APCs; this allows CD28-B7 complex assembly and co-stimulation that restores T cell activation. Ipilimumab also activates Fc receptor-expressing effector cells against CTLA4-expressing Tregs, leading to their elimination via ADCC. (E) Targeting the PD-1:PD-L1 interactions with antibodies: PD-1 on the surface of antigen-educated T cells engages with PD-L1 expressed on melanoma cells and on other immune cells in tumours, leading to T cell anergy and/or deletion. PD-1:PD-L1 complex formation may play a role in tumour immune escape and antibodies targeting the PD-1/PD-L1 blockade may activate T cell responses against melanoma.