Effects of OncoTherad immunotherapy (MRB-CFI-1) on tumor progression and survival of animals with non-muscle invasive bladder cancer (NMIBC): determination of potential mechanisms of action

• Grant number: 18/12626-5
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): October 01, 2018
• Effective date (End): August 31, 2019
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Wagner José Fávaro
• Grantee: Melissa Sena da Silva
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Bladder cancer (CB) is the second most common malignant disease of the urinary tract, and one of the costliest neoplasms for the Unified Health System-Brazil. The primary treatment of non-muscle invasive bladder cancer (NMIBC) is based in transurethral resection, followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG), to decrease recurrence and to prevent tumor progression. However, the use of BCG is associated with side effects of varying intensities, ranging from mild irritative symptoms to severe systemic reaction, which contributes to treatment discontinuation and has a posttreatment recurrence rate of up to 30%. The surgical option, partial or total cystectomy, is often associated with high rates of morbidity and mortality. In addition, for some patients, cystectomy is not an available option due to the presence of concomitant comorbidities. In Brazil, from November 2017 to the present day, the manufacture of the OncoBCG vaccine for the treatment of bladder cancer was suspended by Brazilian Health Regulatory Agency (Anvisa). The lack of the OncoBCG vaccine may have a negative impact on the treatment of patients with bladder cancer. Thus, it is of fundamental importance to develop new therapeutic modalities that prevent the progression of the disease, allow the preservation of the organ and the quality of life of the patients, and finally provide an option for those who are ineligible for cystectomy. Considering the importance of the development of drugs that can be administered intravesically and acting as modulators of the immune system, our research group developed a synthetic nanostructured compound with antitumor and immunological properties called MRB-CFI-1 (Biological Response Modifier - Inorganic Phosphate Complex 1), or OncoTherad. Initial studies in our group demonstrated that in the treatment of chemically induced CBNMI, animals treated with OncoTherad showed significant inhibition of tumor progression in 70% of cases. Furthermore, our studies demonstrated that intravesical immunotherapy with OncoTherad led to the distinct activation of the innate immune system TLRs 2 and 4-mediated, resulting in an increase in the signaling pathway for interferon, which is related to the greater efficacy of this nanocomposite in the treatment of CBNMI in relation to the standard treatment with BCG. Thus, the aims of this study will be to characterize the effects of intravesical immunotherapy with OncoTherad (MRB-CFI-1) on tumor progression and survival of animals with chemically induced CBNMI, as well as to characterize the cellular mechanisms triggered by this therapy.