New Therapeutic Approach for Non-Muscle Invasive Bladder Cancer Based on Monoamine Oxidase-A Inhibition: Use of ImmunoClor

• Grant number: 23/13029-9
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): January 01, 2024
• Effective date (End): December 31, 2024
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Wagner José Fávaro
• Grantee: Cintia Carolina Aguilera Ramos de Andrade
• 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 OncoTherad®, 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 normal and neoplastic bladder tissue. Still, there are no studies that investigated the association of MAO and its inhibitors in improving the responses of immunotherapies in bladder cancer. The chemical inhibition of MAO-A may be a valuable therapeutic approach for NMIBC treatment. Therefore, the aims of this study are to characterize the antitumor and toxic effects of a novel immunotherapeutic product, ImmunoClor, formed by combining the CFI-2 immunotherapeutic platform [Inorganic Phosphate Complex-2, similar to OncoTherad® (MRB-CFI-1)], with a MAO-A inhibitor, clorgiline.