
Development of a Whole-Cell Cancer Vaccine Containing Accumulated Intracellular Interleukin-15: Current Knowledge and Progression
Interest has focused on using potent immunostimulatory cytokines, such as IL-15, as an adjuvant for cancer treatment or as part of a vaccine therapy. This review presents an IFN-α-induced, whole-cell cancer vaccine in mice, contrasts this cancer vaccine with those reported in other studies, and considers its potential use as a human cancer vaccine. Initial studies focused on developing a B16 melanoma vaccine. B16 cells treated for ≥2 weeks with IFN-α become B16α vaccine cells that contain accumulated intracellular IL-15. Intraperitoneal, subcutaneous, and intravenous inoculations of irradiated B16α cells into mice have established adaptive immunity to B16 melanoma and the survival of a substantial fraction of the mice (60% survival with 4 vaccinations and >80% survival with 6 vaccinations). The immunity is specific to B16 melanoma; is active systemically against metastases; demonstrates memory; and, is dependent on the function of macrophages, NK cells, CD4+ helper T cells, and CD8+ cytotoxic T cells, by using corresponding knock-out mice. Thus, B16α cells are “bags” of IL-15 that express melanoma surface antigens. After inoculating irradiated B16α cells into mice, melanomaspecific tissue-infiltrating lymphocytes gather at the inoculation site. When the irradiated B16α cells lyse, they release their accumulated IL-15 as a bolus, activating the melanoma-specific tissue-infiltrating lymphocytes. The activated lymphocytes proliferate and kill B16 melanoma cells throughout the body. While initial studies were focused on developing B16α cells as a melanoma vaccine, the IFN-α treatment protocol has been employed to develop RM-1α cells and P388α cells as vaccines against RM-1 prostate cancer and against P388 lymphocytic leukemia, respectively. The demonstration of efficacious vaccines against multiple cancers supports the general applicability of the IL-15-containing whole-cell vaccine. The relative efficacies of the different vaccines appear to be associated with a relative down-regulation of translation of the IL-15 mRNA. To achieve the full potential of the vaccines, it will be necessary to transfect cancer cells with constructs of IL-15 that negate the down-regulatory mechanisms. Since mouse and human immune systems illustrate many common features of IL-15 function, these studies have high promise of being extended to the creation of human cancer vaccines.
Daniel P Griffin1 and W Robert Fleischmann Jr1*