Combining Radiotherapy and Immunotherapy to Target Survivin in Prostate Cancer

摘要

The goal of this research is to logically integrate immunotherapy (IT) with conventional radiotherapy (RT) to improve the treatment of men with advanced or recurrent prostate cancer. The initial aim is to determine whether local RT of prostate tumors in a preclinical and clinical setting leads to measurable tumor-specific immune responses and whether tumor vaccination can boost these responses leading to better tumor control. Survivin is our tumor antigen of choice, because it seems superior to other prostate tumor antigens. We humanized mouse prostate cancer cell lines (TRAMP C1 and TRAMP C2) to express human HLA-A2.1 and confirmed that these cells express survivin. Interestingly, the tumor cell lines failed to form tumors in transgenic HLA- A2.1 mice and seemed to be immunologically rejected. Nevertheless, we were able to use these humanized TRAMP cells to examine the vaccination responses to human survivin epitopes and to other clinically relevant human prostate cancer associated antigens. Clinical samples were analysed by tetramers to show that circulating survivin-specific CD8+ T lymphocytes were present in prostate cancer patients that they were increased further upon completion of RT. We hypothesize that this is due to increased liberation of antigenic peptides and that IT will not be hindered by RT. In further support of this conclusion, circulating T regulatory cells were not influenced by RT. It is clear is that RT does not induce immune tolerance to survivin nor does it increase suppressor T cells making IT approaches feasible in combination with RT for prostate cancer.