OncoTherad® (MRB-CFI-1) Nanoimmunotherapy: A Promising Strategy to Treat Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer: Crosstalk among T-Cell CX3CR1, Immune Checkpoints, and the Toll-Like Receptor 4 Signaling Pathway.

This study assessed the safety and efficacy of OncoTherad® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients' mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1-2 events. OncoTherad® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1+ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.

Evaluation of the tissue repair process and immunomodulatory action of Platelet-Rich Plasma (PRP) in the treatment of abdominal stretch marks.

The aims of this study were to characterize and to compare the structural alterations of collagen and elastic fibers in the abdominal stretch marks of patients submitted to intralesional and per quadrant (region close to stretch marks) Platelet-Rich Plasma (PRP) treatment, as well as, to establish the possible mechanisms of action of this treatment involving toll-like receptors (TLRs) signaling pathways and growth factors. Incisional biopsies were collected from abdominal stretch marks with a 2 mm diameter punch in female patients, at the beginning of treatment, after 6 and 12 weeks of treatment, and submitted to morphological analyzes of elastic and collagen fibers, and immunohistochemistry for TLRs signaling pathways and growth factors. Our results demonstrated PRP per quadrant treatment was most effective in reducing the area of the abdominal stretch marks, with consequent stimulation of the synthesis and remodeling of collagen and elastic fibers. Also, PRP per quadrant treatment promoted an increase in TLR2 and TLR4 immunoreactivities, with consequent increase in TNF-α, VEGF and IGF-1. Based on the current findings, PRP constitutes a promising therapeutic approach in patients with stretch marks, since it promoted modulation of inflammatory cytokines and growth factors, with consequent remodeling of extracellular matrix, culminating with tissue improvement.

OncoTherad® is an immunomodulator of biological response that downregulate RANK/RANKL signaling pathway and PD-1/PD-L1 immune checkpoint in non-muscle invasive bladder cancer.

INTODUCTION: Bladder cancer is the second most common urinary tract cancer. Above 70% of the occurrence of bladder cancer is superficial (pTis, pTa, and pT1), non-muscle invasive tumor (NMIBC), and the incidence of invasive disease is occasional. Treatments for NMIBC consist of transurethral resection (TUR) and subsequently intravesical immunotherapy with Bacillus Calmette-Guérin (BCG), intending to prevent tumor progression and decrease recurrence. However, 20-30% of these tumors have progression, and 70% have a recurrence after exclusive TUR treatment. The immunomodulator of biological response, OncoTherad®, is an attractive potential to revolutionize cancer therapy. In our previous studies with mice, the results showed that treatment with OncoTherad® reduced 100% of tumor progression in NMIBC through the activation of Toll-Like Receptors' non-canonical pathway. MATERIALS AND METHODS:  In the present study, 36 female C57Bl/6J mice were divided into 6 groups (n = 6/group): Control, Cancer, Cancer + BCG, Cancer + OncoTherad® (MRB-CFI-1), Cancer + P14-16 and Cancer + CFI-1. NMIBC was chemically induced and the treatments were followed for 6 weeks. A week after the last dose of treatment, animals were euthanized, the bladder was collected and routinely processed for immunohistochemical analyses of RANK, RANKL, FOXP3, and PD-1/PD-L1, such as PD-1/PD-L1 western blotting. CONCLUSION: The immunohistochemical results showed that OncoTherad® reduced RANK and RANKL immunoreactivities compared to the cancer group, which indicates a good prognosis. Immunohistochemical and western blotting analyses confirmed that OncoTherad® modulated PD-1/PD-L1 immune checkpoint.

P-mapa, a promisor immunomodulator against tumor cells of colonic tissues: An investigation of the action mechanism over the TLR4 signaling pathway.

Colorectal cancer (CRC) is a multifactorial syndrome that drives to uncontrollable cell division, genetic alterations, and functional alteration. In the present work, we evaluated the immunomodulatory properties of P-mapa, a compound extracted from Aspergillus oryzae fungus, versus Fluorouracil (5-FU) treatment in chemically induced CRC. CRC was induced by DMH in F344 rats. Animals of treated groups receive weekly 15 mg/Kg of 5-FU or 5 mg/Kg of P-mapa, over 10 weeks. Tissues were stained for aberrant crypt foci (ACF) counting and histopathology evaluation, immunostained for TLR4 pathways and quantified for TNFα Cytokine assay. DMH was efficient to induce hyperplastic lesions and ACF. Both treatments reduced significantly ACF formation and tumor aggressiveness. Immunohistochemistry for TLR4 signaling reveals that both treatments had no effect over the TLR4-NFκB signaling pathway. On the other hand, both succeed in increase interferon signaling, with activation of the TRIF-IRF3 pathway and consequently inducing IFNγ synthesis. The present results show the immunomodulatory properties of P-mapa in chemically induced CRC model. P-mapa induced a significant increase in Type-I IFNs synthesis and subsequently immune cell recruitment, resulting in an increase of IFNγ concentration in colorectal mucosa and its inhibitory effects over tumoral growth. In this scenario, P-mapa showed an interesting antitumoral effect by inhibiting tumor growth.