Crosstalk Among T-Cells CX3CR1+, Immune Checkpoints and Monoamine Oxidases in Non-Muscle Invasive Bladder Cancer: Clinical Implications of OncoTherad Nano-Immunotherapy (MRB-CFI-1)

• Grant number: 22/09699-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): November 01, 2022
• Effective date (End): October 31, 2023
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Monaliza Ávila
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Nearly half a century the immunotherapy with Bacillus Calmette-Guerin (BCG) has been the gold standard treatment for non-muscle invasive bladder cancer (NMIBC). However, many patients with high-risk disease experience recurrence, including those who progress and eventually become unresponsive to BCG. For decades, apart from radical cystectomy, few therapeutic options existed for this at-risk population. However, the advent of new immunotherapeutic agents has transformed the treatment of several types of tumors, including urothelial carcinoma. These immunotherapies have shown promising results in the treatment of bladder cancer. In this scenario, our research group developed the OncoTherad® (MRB-CFI-1) immunotherapy, which has shown positive results in the treatment of cancer, especially NMIBC. Based on preclinical, clinical-veterinary and Phase 1/2 clinical studies in humans, OncoTherad® immunotherapy (MRB-CFI-1) represents a new approach to combating high-grade malignant lesions still in the bladder urinary, before spreading to adjacent tissues and organs. However, new immunotherapies, including OncoTheradÒ, have yet to overcome the effectiveness of BCG. Due to the inherent complexity of the immune response, patient selection and the development of biomarkers to guide the identification of patients who will derive the greatest benefit from a given immunotherapy remain critical. Most immunotherapies work by enhancing the antitumor responses of CD8+ T cells, which can be severely limited by the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a key component of the immunosuppressive TME, decrease anti-tumor T cell reactivity in most solid tumors. In recent years, several studies have demonstrated the upregulation of monoamine oxidase A (MAO-A) in neoplastic tissues compared to normal tissues, and MAO-A expression has been associated with metastasis and decreased overall survival in various types of cancers. The role of MAO in bladder cancer is still poorly explored. There are few reports in the literature regarding the functions and types of MAO in neoplastic bladder tissue. This project will aim to characterize the histopathological and molecular effects of OncoTherad® nano-immunotherapy (MRB-CFI-1) in patients with BCG-unresponsive (relapsed, refractory, intolerant) NMIBC, as well as investigate the possible mechanisms of this immunotherapy in the functioning of factors and signaling pathways interrelated and implicated in the complex microenvironment of bladder cancer, constituting an informative panorama about the profile of the inflammatory/immune response to the proposed treatment.