Rethinking Cancer Vaccines to Avoid T-Cell Traps

Cancer vaccines have gained increasing popularity since the US FDA approved the first cancer vaccine, sipuleucel-T, in 2010 and then approved the active specific immunotherapeutic agent, ipilimumab, in 2011. Several other recently reported positive randomized trials have started reversing the seemingly endless flow of failed cancer vaccine trials [1–4]. This has not been a complete reversal, however, with the recent report at ASCO that the Stimuvax trial failed to meet its primary end point in lung cancer; however, there was a significant improvement in overall survival in a large subset of over 800 patients. Since the majority of cancer vaccine trials have been performed in melanoma, this disease entity has endured more than its share of cancer vaccine failures. However, melanoma has taught us more than any other disease about the endogenous immune response to cancer. Specifically, multiple immunogenic peptides have been described from melanoma-specific antigens such as p-mel and MART-1 that efficiently induce and expand T cells with the capacity to recognize and destroy melanoma cells expressing these antigens. It is understandable then why these peptides have been the focus of many early and ongoing clinical trials. As with most vaccines, the antigenic focus of the vaccine must be joined with an immunoadjuvant to enhance its effectiveness. Incomplete Freund’s adjuvant (IFA) is a water-in-oil emulsion specifically designed not only to enhance the immunogenicity of vaccines but also to serve as a slow-release source of antigen to the immune system. IFA has been one of the most commonly utilized cancer vaccine adjuvants to date and has been frequently used with peptide-based vaccines, especially in melanoma trials. Unfortunately, the vast majority of these peptide/IFA vaccine trials have been negative with rare objective clinical