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.

Abstract

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.

Vitamin D, zinc and glutamine: Synergistic action with OncoTherad immunomodulator in interferon signaling and COVID‑19 (Review)

“…Response Modifier -Inorganic Phosphate Complex 1 (MRB-CFI-1, for its acronym in Portuguese), registered as OncoTherad, is a nanometric compound of metallic salts and phosphate and associated with a glycosidic protein, 420-530 nm in size (36)(37)(38)(78)(79)(80). This novel nano-immunotherapy stimulates the immune system to eliminate cancer and could become a promising strategy against SARS-CoV-2.…”

“…The primary treatment for NMIBC is based on surgical transurethral resection followed by intravesical immunotherapy with bacillus Calmette-Guérin (BCG) to avoid tumor progression and decrease recurrence. Preclinical, clinical-veterinary and phase I/II clinical trials have shown that nano-immunotherapy with OncoTherad leads to the distinct stimulation of the innate immune system mediated by TLR2 and TLR4, resulting in an increased activation of the IFN signaling pathway [TLR4, TIR-domain-containing adapter-inducing IFN-β (TRIF), interferon regulatory factor (IRF)-3, IFN-α and -γ], which is associated to the superior efficacy of this nanocompound in the management of NMIBC compared to the standard treatment with BCG (36)(37)(38)82).…”

“…More specifically, the OncoTherad-induced stimulation of the immune system via TLR2 and TLR4 occurs through the phosphorylation of hydroxylated amino acids, such as tyrosine, threonine and serine by compounds that contain phosphate salts (36)(37)(38)(78)(79)(80), resulting in the activation of stimulator of interferon genes (STING), with a consequent increase in the production of IFN-α and IFN-γ. The increase in the production of IFNs mediated by TLRs-2 and 4 promotes the activation of TCD8 + cells, dendritic cells and M1 macrophages, culminating in the superior effectiveness of OncoTherad in the therapy of bladder cancer when compared to BCG (37,38,78,80).…”

“…The increase in the production of IFNs mediated by TLRs-2 and 4 promotes the activation of TCD8 + cells, dendritic cells and M1 macrophages, culminating in the superior effectiveness of OncoTherad in the therapy of bladder cancer when compared to BCG (37,38,78,80). Experiments with rodents (36,38,80) and dogs (38,79,80) have demonstrated that OncoTherad is able to decrease the expression of receptor activator of nuclear factor-κB (RANK) and receptor activator of nuclear factor-κB ligand (RANK-L) system and, as a result, prevent the formation of metastases and/or counteract their progression. In addition, in the treatment of bladder cancer chemically induced in Fisher 344 rats, OncoTherad nano-immunotherapy was shown to increase the immunoreactivities of regulatory proteins, such as phosphatase and tensin homolog (PTEN) and p21, demonstrating the positive contribution of this immunotherapy in the regulation of the cell cycle (80).…”

“…A common mechanism among these compounds, which already exhibit an important synergy, is their ability to modulate the signaling pathways for interferons (IFNs), which are cytokines recognized for their antiviral properties (8,(28)(29)(30)(31)(32)(33)(34)(35). This area of metabolic confluence, dependent on these nutrients, also corresponds to a synthetic nanocompound known as OncoTherad, developed as an antineoplastic and immunomodulator used as therapy for non-muscle invasive bladder cancer (NMIBC) (36)(37)(38). With the objective of designing a joint use, considering a possible enhancement of their efficiencies, the present review article discusses the common properties of these compounds (zinc, vitamin D, glutamine and OncoTherad), considering that when a deficiency occurs, nutrients may become limiting factors of the action of other nutrients and drugs (39).…”