Versatile Prostate Cancer Treatment with Inducible Caspase and Interleukin-12

Abstract

To establish optimized conditions for immunity against prostate cancer, we compared the efficacy of multiple approaches in autochthonous and s.c. transgenic adenocarcinoma of the mouse prostate (TRAMP)-based models. Mice immunized with interleukin (IL)-12-containing apoptotic, but not necrotic TRAMP-C2 cell-based, vaccines were resistant to TRAMP-C2 tumor challenge and re-challenge, independently of the route of vaccination (s.c. or i.p.). Administration of ;-irradiated TRAMP-C2 cells preinfected with adenovirus containing both B7-1 and IL-12 genes, unlike adenovirus containing B7-1 alone, considerably protected C57BL/6 mice from TRAMP-C2 tumor growth and extended the life span of TRAMP mice. Vaccines that included dendritic cells, instead of IL-12, were equally efficient. Whereas injections of ligandinducible caspase-1-and IL-12-containing adenoviruses cured small s.c. TRAMP-C2 tumors, nanopump-regulated delivery of viruses led to elimination of much larger tumors. The antitumor immune responses involved CD4 + -, CD8 + -, and natural killer cells and were strengthened by increasing the number of vaccinations. Intraprostatic administration of inducible caspase-1-and IL-12-containing adenoviruses resulted in local cell death and improved survival of adenocarcinoma-bearing TRAMP mice. Thus, tumor cell apoptosis induced by caspase in situ and accompanied by IL-12 is efficient against prostate cancer in a preclinical model. (Cancer Res 2005; 65(10): 4309-19)

Serum Th1 and Th17 related cytokines and autoantibodies in patients with Posner-Schlossman syndrome

“…IL-12 is an important factor in regulation of innate and adaptive immunity [20]. Tarrant et al reported that increased serum IL-12 could promote the production of IFN-γ and nitric oxide, and further enhance the inflammatory response of autoimmune uveitis [21].…”

Concomitant Tumor and Minor Histocompatibility Antigen–Specific Immunity Initiate Rejection and Maintain Remission from Established Spontaneous Solid Tumors

“…To date, this is the first efficacious treatment for TRAMP mice at an advanced stage of disease (29,30,(33)(34)(35) and the only report of the cure of spontaneous tumors with unmanipulated, unselected donor T lymphocytes. These findings are of particular relevance in the TRAMP model in which the genetic pressure for cancer recurrence is particularly strong (11) and able to induce unresponsiveness of high-affinity tumor-specific T cells (36,37).…”

Role of inflammasomes and their regulators in prostate cancer initiation, progression and metastasis

“…Identification of inflammasome-independent mechanisms of caspase-1 activation would help resolve the function of caspase-1 in prostate cancer. Adenoviruses expressing inducible caspase-1 have been used to treat prostate tumors in mouse models in combination with other molecules [21]. However, the molecular mechanisms of caspase-1-induced apoptosis have not been well characterized.…”