PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab

Abstract

Remarkable clinical responses have been seen in patients with metastatic melanoma with targeted therapy (BRAFi vemurafenib, MEKi) and with modern immune cell-based approaches such as TCR engineered adoptive cell transfer (ACT) and earlier experiences with high-dose IL-2. The proximal mediators of these immune therapies are tumor-reactive CTL. Various mechanisms of resistance to immune-mediated apoptotic signals have been described, including phenotypic changes, effector cell exhaustion, functional tolerance, deficiencies in Ag processing and presentation, and mutation or down-regulation of antigenic epitopes. The immune system and drugs eradicate tumors via apoptosis. Therefore, tumors' resistance to apoptosis may be a determining factor that limits the efficacy of immunotherapies. It is predicted that these therapies have limited efficacy in patients whose melanomas have developed resistance to targeted therapy such as vemurafenib. Upregulation of the immune checkpoint molecule CTLA-4 on activated T cells and its interaction with CD80/86 blocks T cell activation. The fully humanized mAb ipilimumab blocks this interaction, resulting in sustained T cell stimulation. Likewise, the programmed death receptor 1 (PD-1) is another member of the B7:CD28 family of costimulatory molecules that regulates T cell activation, whose ligand (PD-L1) is expressed on melanomas. The human anti-PD-1 mAb, Pembrolizumab, overcomes tolerance, has a favorable pharmacokinetics profile with minimal undesired toxic side effects and has shown remarkable improvement in melanoma therapy. This review focuses on recent advances in the development of various anti-PD-1 checkpoint blockade antibodies and will summarize recent clinical data using immune checkpoint blocking antibodies.

Keywords: CTLA-4; MED14736; PD-1; PD-L1; Pembrolizumab; TCR; apoptosis; immunotherapy; ipilimumab; melanoma; nivolumab; tremelimumab.

Figure 1

Current immunotherapies in the treatment of melanomas. Upon recognition, through interaction of peptide/MHC with TCR/CD8, cytotoxic T cells induce apoptosis in sensitive melanomas via perforin/granzyme or death receptor-mediated (Fas/FasL, TRAIL/DR4, DR5) pathways. Checkpoints blockade (using anti-CTLA-4 and anti-PD-1 mAbs) and ACT of antigen-specific cytotoxic T cells have remarkably improved melanoma treatment. Constitutively hyper-activated anti-apoptotic cell survival pathways (BRAF^V600E, NF-kB, AKT, MAPK, etc.) confer apoptosis-resistance by regulating the expression pattern of pro- and anti-apoptotic gene products, thus, limiting the efficacy of treatment.

Figure 2

CTLA-4 check point blockade in the treatment of melanomas. A. Under normal conditions ligation of Cd28 with B7.1, B7.2 (CD80, CD86) provides signal II for T cell activation. The negative regulatory signaling molecule CTLA-4 competes with CD28 in binding to B7 family ligands. B. CTLA-4 ligation to B7 family ligands inhibits T cell functionality (proliferation, activation, cytotoxic potential). C. mAbs directed against CTL-4 check point regulator inhibit its binding to B7 family ligands, thus, promoting T cell functionality.

Figure 3

PD-1 check point blockade in the treatment of melanomas. (A) Under normal conditions ligation of PD-1 with PDL-1, PDL-2 provides a negative stimulatory signal to T cells, thus, even in the presence of TCR recognition of peptide/MHC complex, T cells are rendered inactive to kill tumor cells. The negative regulatory signaling provided by PD-1 PD-L engagement can be easily blocked by mAbs directed against check point molecules. (B) PDL-1 or (C) PD-1, promoting the functionality of T cell and tumor eradication.