Regulated Apoptosis and Immunogene Therapy for Prostate Cancer
Abstract
The central tenet of this proposal is 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. Scope: Previously created inducible caspases (iCaspases) have been used as the basis of both a prophylactic vaccine and as treatment of pre-existing subcutaneous (sc) and autochthonous TRAMP-derived prostate tumors. While these studies are centered on prostate cancer, they could be extended to other tumor types. Major findings: The combination of iCaspases and lL-12 can completely eliminate small (less than or equal to 40 cu mm) sc tumors and largely eliminate larger (less than or equal to 100 cu mm) tumors while lL-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. Finally, 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. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA442361
Entities
People
- David M. Spencer
- Kevin M. Slawin
Organizations
- Baylor College of Medicine