Role of OncoTherad immunotherapy in the regulation of toll-like receptors-mediated immune system and RANK/RANKL signaling: New therapeutic perspective for non-muscle invasive bladder cancer

• Published in: Journal of clinical oncology Vol. 37; no. 15_suppl; p. e16004
• Main Authors: Fávaro, Wagner José, Iantas, Sonia Regina, Gonçalves, Juliana Mattoso, Dias, Queila Cristina, Reis, Ianny Brum, Billis, Athanase, Duran, Nelson, Alonso, João Carlos Cardoso
• Format: Journal Article
• Language: English
• Published: 20.05.2019
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2019.37.15_suppl.e16004

Abstract only e16004 Background: The new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom Bacillus Calmette-Guerin (BCG) has failed or is contraindicated are recently increasing due to the development of new drugs. In this scenario, a new perspective is represented by OncoTherad immunomodulator. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein, developed by University of Campinas/ Brazil, which exhibits antitumor properties. This study detailed and characterized the therapeutic effects of OncoTherad based on activation of Toll-Like Receptors (TLRs) signaling pathways and regulation of receptor activator of nuclear factor kβ (RANK)/RANK ligand (RANKL) cytokine system in an animal model of NMIBC, as well as, compared these effects with BCG treatment. Methods: Fisher 344 female rats were submitted to NMIBC induction with N-methyl-N-nitrosourea (MNU). MNU treated animals were further divided into 3 groups (10 animals per group): the NMIBC group received 0.30 mL of saline solution; the NMIBC-BCG group received of 2 mg/mL of BCG; the NMIBC-OncoTherad group received 20 mg/Kg dose of OncoTherad. All animals were treated intravesically every other week for 6 weeks. Results: Our results demonstrated that OncoTherad intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway, which was more effective (80.0%) in the NMIBC treatment, when compared to BCG treatment (20.0%). Interferon signaling pathway activation induced by OncoTherad led to increase of iNOS expression, resulting in apoptosis and histopathological recovery. Also, OncoTherad immunotherapy decreased RANK/RANKL expression, resulting in reduced regulatory T (Treg) cells. Conclusions: The decreased of RANK/RANKL expression by OncoTherad was fundamental to up-regulation interferon signaling pathway and in suppresion of abnormal cell proliferation. Thus, OncoTherad immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of BCG-refractory or relapsed patients.