Dendritic cell vaccination in melanoma patients: From promising results to future perspectives

Abstract

Dendritic cells (DCs) play an important role in the induction of antitumor immunity. Therefore, they are used as anti-cancer vaccines in clinical studies in various types of cancer. DC vaccines are generally well tolerated and able to induce antigen-specific T cell responses in melanoma patients. After DC vaccinations, functional tumor-specific T cells are more frequently detected in stage III melanoma patients, as compared to patients with advanced melanoma, indicating that the tumor load influences immunological responses. Furthermore, long-lasting clinical responses were rarely seen in metastatic melanoma patients after DC vaccination. Since more potent treatment options are available, e.g. immune checkpoint inhibitors and targeted therapy, DC vaccination as monotherapy may not be preferred in the treatment of advanced melanoma. However, encouraging results of DC vaccines combined with ipilimumab have been reported in advanced melanoma patients with an objective response rate of 38%. DC vaccines show promising clinical results in stage III patients, although clinical efficacy still needs to be proven in a phase 3 trial. The clinical and immunological results of DC vaccination in stage III melanoma patients might be further improved by using naturally circulating DCs (myeloid DCs and plasmacytoid DCs) and neoantigens to load DCs.

Keywords: Dendritic cell vaccination; immune checkpoint inhibitors; immune response; melanoma; naturally circulating dendritic cells; neoantigens.

Figure 1.

Immune therapy and targeted therapy of melanoma. ^aBy injecting activated dendritic cells (DCs) loaded with tumor antigens, DC vaccination aims to induce tumor associated antigen-specific T cells. Antigen presentation by DCs and co-stimulation signals (B7-CD28) result in T cell activation and proliferation. ^bTo keep an immune response in control, CTLA-4 is then up regulated on the surface of T cells, which binds stronger to B7 than CD28 and causes an inhibitory signal. Blocking CTLA-4 with monoclonal antibodies (ipilimumab) enhances T cell activation. ^cBinding of PD-1 on the T cells to PD-L1 on the tumor results in downregulation of effector functions of T cells, which inhibits the killing of tumor cells. Blockade of this ligation by anti-PD-1 antibodies (nivolumab, pembrolizumab) makes it possible for T cells to maintain their antitumor functions, which allow them to kill tumor cells. ^dBRAF is a kinase that is part of the RAS-BRAF-MEK-ERK mitogen-activated protein kinase (MAPK) pathway of cell proliferation. The tumors of approximately 40–60% of advanced melanoma patients harbor activating BRAF V600 mutations. The mutated kinase is constitutively active, which results in unregulated cell proliferation. This process can be blocked by selective BRAF inhibitors (vemurafenib, dabrafenib). ^eSingle-agent BRAF inhibition results commonly in progressive disease due to acquired resistance, which is commonly caused by genetic escape mechanisms resulting in MAPK pathway independant signaling. Upfront inhibition of both MEK (cobimetinib, trametinib) and the mutated BRAF kinases might counteract this form of resistance. (+) indicates a stimulatory effect; (−) indicates an inhibitory effect. Abbrevations: CTLA-4, cytotoxic T-lymphocyte-associated antigen 4, MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; TCR, T cell receptor.