Melanoma vaccines: trials and tribulations

Robert O Dillman<sup>1,2

1</sup>Hoag Cancer Institute and Hoag Institute for Research and Education, Newport Beach, CA, USA; ²University of California Irvine, Irvine, CA, USA

Abstract: Metastatic melanoma has been a target of immunotherapy for more than 4 decades. Three immunotherapeutics have received regulatory approval for treating melanoma: interferon-alpha, interleukin-2, and ipilimumab. The antitumor mechanisms of these products depend on enhancing existing immune responses, including autoimmune effects. The combination of autologous, cytotoxic T-lymphocytes plus high-dose interleukin-2 is a promising patient-specific therapy, but has limited clinical application. Other approaches include vaccines targeting melanoma-associated antigens, and patient-specific vaccines that utilize autologous tumor. Non-patient-specific vaccine approaches target melanocyte differentiation antigens (eg, tyrosinase, Melan-A, gp100), antigens identified by cytotoxic T-lymphocytes (eg, NY-Eso-1, Melan-A/Mart-1, Mage-3), and antigens originally identified by murine monoclonal antibodies (gangliosides, gp97, gp225). Self-renewing cells in tumor cell lines may represent tumor stem cells, but vaccines derived from allogeneic tumor cell lines have yielded disappointing results in randomized trials. Patient-specific vaccines can be derived from bulk autologous tumor or autologous tumor cell lines, and intratumoral injections of immunostimulatory fusion products have shown promise. While technically more complex to manufacture, patient-specific vaccines derived from autologous tumor cell lines have the potential to target tumor stem cells and overcome interpatient tumor cell heterogeneity. This article reviews sources of melanoma-associated antigens, costimulatory agents, and clinical trial results for various melanoma vaccines. Comparing Phase II trials is difficult because of the wide range of vaccine strategies and the differences in study patient populations; therefore, randomized trials are necessary to prove the efficacy of such products. Therapeutic vaccines are more likely to enhance, rather than replace, other anti-melanoma immune therapies. In particular, effective vaccines may be synergistic with products that block T-cell immune checkpoint molecules such as ipilimumab and monoclonal antibodies that interfere with programmed death ligand-receptor interactions.

Keywords: melanoma, vaccines, melanoma-associated antigens, melanoma stem cells, dendritic cells, GM-CSF, checkpoint molecules