Therapeutic and toxicological effects of OncoTherad (MRB-CFI-1) immunotherapy in patients with BCG-refractory or relapsed non-muscle invasive bladder cancer

Abstract

Bladder cancer (BC) represents the second most common malignant disease of the urinary tract, and one of the neoplasms that have the highest costs for the Unified Health System. The primary treatment of non-muscle invasive bladder cancer (NMIBC) is based on surgical treatment using transurethral resection, followed by intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), to reduce recurrence and prevent tumor progression. However, the use of BCG is associated with side effects of varying intensities, from mild irritative symptoms to severe systemic reaction, which contributes to the interruption of treatment, in addition to presenting a post-treatment 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, the manufacture and distribution of the OncoBCG vaccine suffers from constant interruptions. The lack of the OncoBCG vaccine can negatively impact the treatment of patients with bladder cancer. Thus, the development of new therapeutic modalities that prevent the progression of the disease, allow the preservation of the organ and the quality of life of patients and, finally, provide an option for those who are ineligible for cystectomy, is of fundamental importance. Considering the importance of developing drugs that can be administered intravesically and that act as modulators of the immune system, our research group developed a nanostructured synthetic compound with antitumor and immunological properties, called MRB-CFI-1 (Biological Response Modifier - Inorganic Phosphate Complex 1), or OncoTherad. The preclinical and clinical-veterinary studies of our group showed that in the treatment of chemically induced CBNMI in rodents and spontaneous in dogs, animals treated with OncoTherad showed significant inhibition of tumor progression in 70% - 80% of cases. In addition, our studies demonstrated that intravesical immunotherapy with OncoTherad led to distinct activation of the innate immune system mediated by TLRs 2 and 4, resulting in an increase in the signaling pathway for interferon, which is related to the greater effectiveness of this nanocomposite in the treatment of NMIBC compared to BCG treatment. Thus, the aims of this study are to evaluate the therapeutic effects of OncoTherad immunotherapy in patients with BCG-refractory or relapsed NMIBC, through analyzes of pathological complete response, relapse-free survival and progression, duration of response and time to disease recurrence during the 24-month follow-up. Moreover, this study aims to investigate the cellular mechanisms triggered by this therapy, as well as its possible local and systemic toxic effects. (AU)