Regulated Apoptosis and Immunogene Therapy for Prostate Cancer

摘要

The central tenet of this proposal was that methods to effectively trigger apoptosis within prostate tumors can both reduce tumor burden and elicit adaptive immunity, provided a pro-inflammatory environment can be created. We created inducible caspases (iCaspases) that were the basis of both a prophylactic vaccine and as a treatment for pre-existing subcutaneous (sc) and autochthonous (TRAMP) prostate tumors. While these studies were centered on prostate cancer, they should also be relevant to other tumor types. Major findings: The combination of iCaspases and IL-12 can completely eliminate small (less than or equal to 40 mm3) sc tumors and largely eliminate larger (less than or equal to 100 mm3) tumors while IL-12 alone had minimal effect and iCaspase alone had no significant effect. Anti-tumor efficacy mirrored expansion of anti-tumor cytotoxic T lymphocytes and IFN-(Gamma)-producing cells from splenocytes of vaccinated animals. Further, orthotopic injections into the prostates of tumor-bearing TRAMP mice trigger apoptosis, secondary necrosis and inflammation, and significantly extend survival. In transgenic animals, the hK2- E3/P, PSA-E2/P and ARR2PB composite promoters are highly active in prostate epithelial cells and are largely prostate specific; however, they are somewhat attenuated as tumor progression occurs, potentially reducing efficacy in tumor cells. Finally, we developed ubiquitous and tissue-specific clinical candidate vectors that are being tested for a potential clinical trial. This work lays the groundwork for an 'off-the-shelf' injectable immunogene therapy that could treat prostate cancer as a neoadjuvant therapy or possible less mutagenic treatment for metastatic disease.