Department of Structural and Functional Biology, Institute of Biology - University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Department of Diagnosis and Surgery, School of Dentistry - São Paulo State University (UNESP), Araraquara, São Paulo, Brazil.
Int Immunopharmacol. 2023 Oct;123:110723. doi: 10.1016/j.intimp.2023.110723. Epub 2023 Jul 31.
Patients with non-muscle invasive bladder cancer (NMIBC) that are unresponsive to Bacillus Calmette-Guérin (BCG) have historically had limited treatment options. A new perspective is represented by OncoTherad® (MRB-CFI-1) immunotherapy, a nanostructured inorganic phosphate complex associated with glycosidic protein, developed by the University of Campinas in Brazil. Previous studies have shown that Platelet-Rich Plasma (PRP) also acts on immune activation and exerts antitumor effects. This study characterized the effects of the OncoTherad® associated with PRP in the treatment of NMIBC chemically induced in mice. When treated intravesically with PRP only, mice showed 28.6% of tumor progression inhibition rate; with OncoTherad® 85.7%; and with OncoTherad®+PRP 71.4%. Intravesical treatments led to distinct activation of Toll-like Receptors (TLRs) 2 and 4-mediated innate immune system in the interleukins (canonical) and interferons (non-canonical) signaling pathways. OncoTherad® isolated or associated with PRP upregulated TLR4 and its downstream cascade mediators as well as increased interleukins 6 (IL-6) and 1β (IL-1β), and interferon-γ (IFN-γ). In this way, the NMIBC microenvironment was modulated to a cytotoxic profile correlated with the IL-1β increase by stimulating immune pathways for IFN-γ production and consequent cytotoxic T lymphocytes (as CD8+ T-cells) activation and regulatory T-cells (Tregs) reduction. In addition, PRP did not trigger carcinogenic effects through the biomarkers evaluated. Considering the possibility of personalizing the treatment with the PRP use as well as the antitumor properties of OncoTherad®, we highlight this association as a potential new therapeutic strategy for NMIBC, mainly in cases of relapse and/or resistance to BCG.
患有非肌肉浸润性膀胱癌（NMIBC）且对卡介苗（BCG）无反应的患者，其治疗选择历来有限。巴西坎皮纳斯大学开发的一种新型免疫疗法OncoTherad®（MRB-CFI-1）为这种情况带来了新的视角。这种免疫疗法是一种与糖基蛋白相关的纳米结构无机磷酸盐复合物。先前的研究表明，富含血小板的血浆（PRP）也可以激活免疫反应并发挥抗肿瘤作用。本研究旨在探究 OncoTherad®联合 PRP 对化学诱导的 NMIBC 小鼠模型的治疗效果。单独经膀胱内给予 PRP 治疗时，肿瘤进展抑制率为 28.6%；而单独给予 OncoTherad®时，肿瘤进展抑制率为 85.7%；联合应用 OncoTherad®和 PRP 时，肿瘤进展抑制率为 71.4%。经膀胱内给予这三种治疗药物均可在白细胞介素（经典）和干扰素（非经典）信号通路中激活 Toll 样受体（TLR）2 和 4 介导的固有免疫系统。OncoTherad®单独或联合 PRP 均可上调 TLR4 及其下游级联介质，增加白细胞介素 6（IL-6）和 1β（IL-1β）以及干扰素-γ（IFN-γ）的产生。通过刺激产生 IFN-γ的免疫途径，从而激活细胞毒性 T 淋巴细胞（如 CD8+T 细胞）并减少调节性 T 细胞（Tregs），这种方式可以调节 NMIBC 微环境，使其向细胞毒性表型转变，与 IL-1β的增加相关。此外，通过评估的生物标志物，PRP 并未引发致癌作用。鉴于 PRP 的使用可能具有个体化治疗的潜力，且 OncoTherad®具有抗肿瘤特性，因此我们强调这种联合应用可能成为 NMIBC 的一种新的潜在治疗策略，特别是在对 BCG 复发和/或耐药的情况下。
