Anti-PD-1 and Novel Combinations in the Treatment of Melanoma-An Update

Abstract

Until recently, distant metastatic melanoma was considered refractory to systemic therapy. A better understanding of the interactions between tumors and the immune system and the mechanisms of regulation of T-cells led to the development of immune checkpoint inhibitors. This review summarizes the current novel data on the treatment of metastatic melanoma with anti-programmed cell death protein 1 (PD-1) antibodies and anti-PD-1-based combination regimens, including clinical trials presented at major conference meetings. Immune checkpoint inhibitors, in particular anti-PD-1 antibodies such as pembrolizumab and nivolumab and the combination of nivolumab with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab can achieve long-term survival for patients with metastatic melanoma. The anti-PD-1 antibodies nivolumab and pembrolizumab were also approved for adjuvant treatment of patients with resected metastatic melanoma. Anti-PD-1 antibodies appear to be well tolerated, and toxicity is manageable. Nivolumab combined with ipilimumab achieves a 5 year survival rate of more than 50% but at a cost of high toxicity. Ongoing clinical trials investigate novel immunotherapy combinations and strategies (e.g., Talimogene laherparepvec (T-VEC), Bempegaldesleukin (BEMPEG), incorporation or sequencing of targeted therapy, incorporation or sequencing of radiotherapy), and focus on poor prognosis groups (e.g., high tumor burden/LDH levels, anti-PD-1 refractory melanoma, and brain metastases).

Keywords: BEMPEG; IDO1; LAG-3; PD-1; PD-L1; T-VEC; acral melanoma; adjuvant therapy; brain metastases; combination therapies; desmoplastic melanoma; melanoma; mucosal melanoma; neoadjuvant therapy; novel combinations; uveal mealnoma.

Figure 1

Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) antibodies: Mode of action. Peptides derived from tumor-associated antigens (TAA) are presented by the major histocompatibility complex (MHC) on the surface of cancer cells or DCs and recognized by T cells via their T-cell receptor (TCR). The co-stimulatory molecules B7-1 (or CD80) and B7-2 (or CD86), which are required for T-cell priming, provide an additional signal. T-cell activation leads to upregulation of CTLA-4 on T cells. Binding of CTLA-4 to B7 receptors of dendritic cells results in inhibition of T-cell activation. Anti-CTLA-4 blocking antibodies restore T-cell stimulation in the lymph nodes. Following long-term stimulation, the PD-1 receptor is upregulated by T cells. PD-L1 expressed on cancer cells binds to PD-1 receptors on T cells, which leads to their inhibition. PD-1/PD-L1 antibodies enhance the functional properties of effector T cells at the tumor site. (Reference: Figure adapted from Ribas A [1] and created by F.F. Gellrich).

Figure 2

Bempegaldesleukin expands and activates cluster of differentiation (CD)8+ effector T cells and natural killer cells over regulatory T cells. Bempegaldesleukin (BEMPEG; NKTR-214) is a human recombinant inteleukin-2 (IL-2) attached to six releasable polyethylene glycol (PEG) chains that alter its pharmacokinetics and its receptor binding. When fully PEGylated, NKTR-214 is a prodrug with no biological activity. In vivo, the PEG chains slowly release to generate active IL-2 conjugates with limited binding to the IL-2Rα subunit, thereby favoring the dimeric βγ-IL-2 receptor (IL-2Rβγ; CD122). Consequently, NKTR-214 is selectively stimulating CD8+ T cells and natural killer (NK) cells over the undesirable T regulatory cells (Treg) [25]. (Reference: Figure adapted from Charych D [26] and created by F.F. Gellrich).

Figure 3

T-VEC—mechanism of action. T-VEC is a type 1 herpes simplex virus genetically modified by the deletion of two non-essential viral genes. The functional deletion of the gene herpesvirus neurovirulence factor (ICP34.5) attenuates viral pathogenicity and enhances tumor-selective replication. Inside a normal cell, the virus is unable to replicate. In tumor cells, the virus replicates and induces granulocyte-macrophage colony-stimulating factor (GM-CSF). The lysed tumor cells release viruses, GM-CSF and TAAs. GM-CSF attracts DCs that process and present TAAs to T cells resulting in an efficient induction and activation of tumor-reactive T cells [27]. (Reference: Figure adapted from Andtbacka R [27] and created by F.F. Gellrich).