Dendritic Cells (DC) Vaccine for Metastatic Melanoma

Historically, metastatic melanoma has been associated with a poor prognosis. Recently, numerous immunotherapeutic agents, particularly checkpoint inhibitors, have moved to the forefront of therapy. Checkpoint inhibitors such as ipilimumab, pembrolizumab, and nivolumab have revolutionized the treatment of melanoma. Despite this, not all patients respond to checkpoint inhibitors, and even patients who initially respond to checkpoint inhibitor therapy often later relapse (median response duration of 2 years); complete responses remain uncommon. Thus, more effective immunotherapies are clearly needed. The concept of administering dendritic cell (DC)-based vaccines to prompt an immune response against tumor cells has shown promise in the treatment of advanced cancers. Sipuleucel-T, now FDA-approved for the treatment of advanced prostate cancer, is one such vaccine that consists of autologous antigen-presenting cell (APC) activated ex vivo by a fusion protein consisting of the antigen prostatic acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor (GM-CSF). Although response rates to Sipuleucel-T are low, recent studies suggest that DC vaccines have the potential to improve survival by increasing the breadth and diversity of melanoma-specific T cells. It is known that the method of antigen (Ag) delivery is important for the success of DC vaccines, but it remains unclear which method is most effective in producing antitumor responses. Approaches tested clinically include pulsing with HLA-restricted defined peptide Ags, loading with purified proteins, transfecting with mRNA, engineering with Ag-encoding viral vectors, and using autologous tumor cells or allogeneic cell lines directly as sources of Ag. Efficacy can be measured in vivo using surrogate endpoints, such as development of tumor-specific delayed-type hypersensitivity (DTH) reactions. Prolonged survival of vaccinated melanoma patients has been reported to correlate with induction of positive DTH tests. Antitumor activity may also be assessed by ELISpot analysis of the frequency of tumor-Ag specific IFNγ-producing T cells. To assess the quality of the DC vaccines, surrogate markers of DC function including maturation markers, co-stimulatory molecule expression, and IL12p70 production, a critical cytokine in antitumor response, can be measured