ABSTRACT
PURPOSE: Patients with non-muscle invasive bladder cancer recurrence after 2 induction courses of BCG are eligible for radical cystectomy. So, in the last years research to discover new drugs for the management of non-muscle invasive bladder cancer recurrence after failure of first and second line therapy is ongoing. In accordance to the results obtained with BCG, whose mechanism depends on the induction of the T helper 1 (TH1) immune response, we investigated the activity of a Toll-like receptor (TLR) 2 ligand, named Helicobacter Pylori Neutrophil Activating Protein (HP-NAP), that we recently demonstrated being able of enhancing the differentiation of Th1 cells, both in vitro and in vivo, because of its ability to create an IL-12 enriched milieu. MATERIALS AND METHODS: We show here, in a mouse model of bladder neoplasm implants, that local administration of HP-NAP decreases tumor growth by inducing tumor necrosis. RESULTS: The result is joined up with a massive cluster of both CD4+ and CD8+ IFN-γ+ cells, within neoplasm and regional lymph nodes. It is of note that HP-NAP-treated tumors show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. CONCLUSIONS: The present study suggests that the activity of HP-NAP against urothelial tumor burden warrants subsequent in vivo studies.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Angiogenesis Inhibitors/therapeutic use , Bacterial Proteins/therapeutic use , Carcinoma, Transitional Cell/therapy , Immunotherapy , Urinary Bladder Neoplasms/therapy , Adjuvants, Immunologic/administration & dosage , Administration, Intravesical , Angiogenesis Inhibitors/administration & dosage , Animals , Bacterial Proteins/administration & dosage , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Transitional Cell/blood supply , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/immunology , Carcinoma, Transitional Cell/pathology , Cell Movement/drug effects , Helicobacter pylori/chemistry , Humans , Lymph Nodes/immunology , Lymphocytes, Tumor-Infiltrating/drug effects , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness , Neoplasm Proteins/agonists , Neovascularization, Pathologic/drug therapy , Toll-Like Receptor 2/agonists , Tumor Burden , Urinary Bladder Neoplasms/blood supply , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Intravesical Bacillus Calmette-Guérin (BCG) is the gold standard treatment for intermediate and high-risk non-muscle-invasive bladder cancer. BCG therapy is the most successful example of immunotherapy in cancer. Unfortunately, the treatment-related side effects are still relevant. Furthermore, non-responder patients are candidate to radical cystectomy in the absence of valuable alternative options. These aspects have prompted the search for newer biological response modifiers (BRM) with a better benefit/side effects ratio. The toll-like receptor (TLR) 2 ligand, Helicobacter pylori protein HP-NAP, has been shown to deserve a potential role as BRM. HP-NAP is capable of driving the differentiation of T helper (Th) 1 cells, both in vitro and in vivo, because of its ability to create an IL-12-enriched milieu. Herein, we report that local administration of HP-NAP decreases tumour growth by triggering tumour necrosis in a mouse model of bladder cancer implant. The effect is accompanied by a significant accumulation of both CD4+ and CD8+ IFN-γ-secreting cells, within tumour and regional lymph nodes. Noteworthy, HP-NAP-treated tumours show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. Our findings strongly indicate that HP-NAP might become a novel therapeutic "bullet" for the cure of bladder tumours.
