IL15-VAX: A prostate cancer cellular vaccine expressing IL-15 and IL-15Rα

Interleukin-15 (IL-15) is a pleiotropic cytokine that induces the differentiation and proliferation of T, B and NK cells, enhances activity of CD8+ cytolytic T cells, helps maintain CD44hiCD8+ memory T cells, and stimulates immunoglobulin synthesis by B cells. There has been increasing interest in using IL-15 for immunotherapy of cancer. The majority of IL-15 is membrane bound by the alpha chain of its receptor (IL-15Rα). IL-15Rα then trans-presents IL-15 to the β,γ-receptor to initiate signaling. This trans-presentation occurs between antigen presenting cells and immune effector cells. In creating IL15-VAX we genetically engineered tumor cells to express both IL-15 and IL-15Rα so that they can directly activate effector cells. To do this we constructed two E1, E3 deleted adenoviruses expressing murine IL-15 (Ad.mIL-15) or IL-15Rα (Ad.mIL-15Rα) and ex-vivo transduced murine TRAMP-C2 prostate cancer cells at an MOI of 100 PFU/cell. We demonstrated that these cells were able to express functional IL-15. When these cells were subcutaneously implanted into C57BL/6 mice we found that expression of IL-15 and IL-15Rα significantly impaired or prevented tumor growth at 30 days when compared to Ad.null modified TRAMP-C2 cells (mean volume- 160 ±160 mm3 vs. 1179 ±183 mm3, p <0.05). Next we looked at whether vaccination with IL-15 and IL-15Rα expressing TRAMP-C2 cells (IL15-VAX) could induce tumor specific immune responses against distant tumor. TRAMP-C2 cells were transduced with Ad.IL-15 and Ad.IL-15Rα as before, and then treated with mitomycin C to prevent proliferation. TRAMP-C2 cells transduced with Ad.null (null-VAX) was used as a control. C57BL/6 mice were vaccinated with a single subcutaneous injection of 1 x 106 cells into their hind limb. Fifteen days later the mice were challenged on the opposite flank with 1 x 106 unmodified TRAMP-C2 cells and evaluated for tumor growth. Animals vaccinated with IL15-VAX had significantly reduced tumor growth compared to those vaccinated with Ad.null resulting in a prolongation of survival. At 25 days post-tumor implantation, null-VAX tumors had a mean volume of 1611 ±235 mm3 while those treated with IL15-VAX were 751 ±274 mm3(p<0.05). IL15-VAX induced TRAMP-C2 specific CTL killing and γ-IFN release in ex-vivo assays. TRAMP tetramer positive CD8+ cells were also detected in animals vaccinated with IL15-VAX whereas they were not detected in animals treated with null-VAX. We also showed that the vaccine effect was tumor specific with IL15-VAX with no anti-tumor effect in a non-related MC38 colon cell line. Conclusion: IL15-VAX successfully inhibited the growth of prostate TRAMP-C2 cells and improved survival by inducing tumor specific cell-mediated immune responses.