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Modulation of the Tumor Microenvironment in Non-Muscle-Invasive Bladder Cancer by OncoTherad® (MRB-CFI-1) Nanoimmunotherapy: Effects on Tumor-Associated Macrophages, Tumor-Infiltrating Lymphocytes, and Monoamine Oxidases - Beyond the Abstract

Non-muscle invasive bladder cancer (NMIBC) remains a highly challenging malignancy in urology due to its high recurrence rates and significant potential for progression to more aggressive forms.1,2 Despite Bacillus Calmette-Guérin (BCG) being the gold-standard treatment for NMIBC,2 up to 40% of patients are refractory to BCG, frequently resulting in the need for radical cystectomy.2,3,4 These limitations underscore the need for novel therapeutic strategies for patients who are unresponsive to BCG.

Our study explores nanoimmunotherapy as a promising approach for modulating the tumor microenvironment (TME) in NMIBC, specifically focusing on OncoTherad® (MRB-CFI-1), a novel immunomodulatory therapy. OncoTherad® (MRB-CFI-1) is a nano-immunotherapy developed by our research group at the State University of Campinas (Campinas, SP, Brazil), with patents granted in Brazil (BR102017012768B1), the USA (US11572284B2, US11136242B2), and Europe (EP3626746B1). This formulation combines inorganic phosphate, metal salts, and glycosidic protein (P14-16),5,6 targeting TME reprogramming via Toll-Like Receptor 2 and 4 (TLR-2 and TLR-4) activation, which enhances innate and adaptive immune responses. This mechanism promotes the production of interleukins, interferons, and the recruitment of cytotoxic T lymphocytes.5,6

Our findings underscore the importance of immune cell modulation within the TME, particularly through interactions among tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs). These immune cells, rather than being passive entities, play an active role in tumor dynamics, immune evasion, and therapeutic resistance. Targeting key molecules, enzymes, and immune pathways has shown the potential to reprogram the TME, thus restoring immune surveillance and improving the host’s ability to target tumor cells (Figure 1).


Figure 1: Mechanism of Action of OncoTherad® (MRB-CFI-1) in Tumor Microenvironment Modulation and Immune Activation in Non-Muscle Invasive Bladder Cancer.

A notable outcome of our study is the demonstrated plasticity of the TME and its potential for therapeutic reprogramming. OncoTherad® (MRB-CFI-1) significantly altered TAM behavior, shifting it from a pro-tumorigenic phenotype toward one that supports antitumor immunity (Figure 1). Treatment also reduced regulatory T-cell populations, further enhancing immunosurveillance (Figure 1). Additionally, the activation of TILs was observed, which is crucial for establishing an effective immune response. This evidence suggests that nanoimmunotherapy may not only provide direct anti-cancer effects but may also augment the efficacy of existing treatments, such as BCG therapy.

Our study also highlights the role of monoamine oxidases (MAOs) in the regulation of immune responses within the TME. MAO isoenzymes A and B, primarily found in the central nervous system, catalyze the conversion of biogenic amines into ketones and aldehydes.7,8 Recent studies have demonstrated overexpression of MAOs in various cancers, including prostate,10,11 lung,12 and colon cancers.13 MAO inhibition has shown promise in reducing tumor size and progression in these types.10,14,15 Our findings align with this evidence, revealing MAO-B overexpression in NMIBC and demonstrating that OncoTherad® (MRB-CFI-1) decreases MAO-B immunoreactivity, although it does not affect MAO-A. These results suggest that MAO inhibition may represent a valuable therapeutic target for NMIBC.

An additional contribution of our study is the development of a personalized immune score, designed to assess immune cell composition and activation within the TME of NMIBC patients treated with OncoTherad® (MRB-CFI-1). This immune score quantifies key immune populations, including TAMs and TILs, before and after treatment. Through biomarker analysis and histological data, we identified immune profiles correlating with treatment response and recurrence risk. Our findings demonstrated a shift from low/medium to high immune scores, which correlated with improved recurrence-free survival. This immune score provides an objective method for evaluating the TME, supporting personalized therapeutic strategies that align with each patient’s unique immune profile, and allowing clinicians to tailor treatments. Furthermore, the immune score offers a valuable tool for monitoring immunomodulatory therapies, providing a way to track immune profile changes and predict long-term outcomes.

As immunotherapy continues to advance, our results emphasize the need for personalized, immune-targeted treatments for patients who are refractory or intolerant to traditional therapies, such as BCG. The future of NMIBC treatment lies in the ability to manipulate the immune microenvironment to foster effective and durable anti-tumor immunity.

Written by: Gabriela Cardoso de Arruda Camargo, PhD & Wagner José Fávaro, PhD

Laboratory of Urogenital Carcinogenesis and Immunotherapy (LCURGIN), Universidade Estadual de Campinas (UNICAMP), São Paulo, Brazil.

References:

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