3. Discussion
high-grade NMIBC, SWOG, comorbidity, death, tumor, NMIBC, melanoma, toxicity, infections, bladder cancer, urinary bladder carcinoma
DISEASE PROGRESSION, ADVERSE EFFECTS, TUMOR, MELANOMA, POSTOPERATIVE COMPLICATIONS, ADVERSE EVENTS, PROLIFERATION, DISEASE, INFECTIONS, METASTATIC BLADDER CANCER, METASTATIC DISEASE, TUMOR PROGRESSION, ADHESION, BLADDER CANCER, PSEUDOMONAS, ADVERSE EVENT, URINARY BLADDER CARCINOMA
NMIBC is a diverse condition featuring varying progression and relapse rates which are influenced by several clinical and pathological factors [A critical aspect to be taken into consideration in cases of NMIBC relapse, despite adequate BCG therapy application, lies in whether there is a large enough window of time to explore alternative treatment options before contemplating radical cystectomy. Evidence available in the literature has suggested that most patients have approximately one year before experiencing prognosis decline [In cases where intravesical treatment options prove ineffective, the recommended course of action is radical cystectomy with intestinal diversion. While radical cystectomy has the potential to halt local disease progression, it is accompanied by a substantial risk of postoperative complications, a diminished quality of life for patients, and the potential for overtreatment of individuals whose disease may not be significantly advanced. Furthermore, not all patients are suitable candidates for cystectomy due to factors such as advanced age or the presence of severe comorbidities. Considering the life-altering consequences and the adverse impact on quality of life associated with radical cystectomy, a significant number of patients opt to decline this surgical procedure. Consequently, there exists an urgent need for the development of innovative therapies that can offer a non-surgical second-line treatment option.The BCG non-response point is a crucial time for patients. It is well-established that a third BCG therapy course provides minimal benefit and means the option for undergoing aggressive second-line therapy over cystectomy can potentially lead to tumor progression, among other unfavorable outcomes. On the other hand, radical cystectomy is associated with increased comorbidity rates and may represent over-treatment. Therefore, it is imperative to engage in comprehensive and careful discussions with patients before making these life-changing decisions. Regrettably, guidelines provided by the American Urological Association (AUA) provide limited guidance in this context. Given the scarcity of robust data, many experts in the NMIBC field see cystectomy as the safest option for patients with BCG-non-responsive high-grade NMIBC and for those with high-grade NMIBC who are unable to tolerate full-dose BCG induction and maintenance therapy.In addition to challenges related to BCG’s toxicity and therapeutic ineffectiveness in high-grade NMIBC patients, the ongoing global shortage in BCG production, as well as its distribution disruptions, contribute to significantly worsening patients’ prognoses. The current BCG shortage has forced clinics to implement rationing and prioritization strategies, and it may have contributed to increase disease relapse and progression rates among NMIBC patients [Only two NMIBC treatments were approved by the United States Food and Drug Administration (FDA) in the past three decades. Valrubicin, which is classified as anthracycline, was granted FDA approval in 1998. It was followed by pembrolizumab, which is an immune checkpoint inhibitor immunotherapy approved in 2020 [Nowadays, second-line treatment options available for BCG-unresponsive NMIBC cases are less than ideal. Although several conventional chemotherapeutic agents, such as gemcitabine, mitomycin, gemcitabine combined with mitomycin, docetaxel, and valrubicin, have been explored, none of them was superior to BCG and remains under investigation. Studies focusing on bladder preservation therapies after BCG relapse reported RFS rates lower than 25% after two years based on single-agent intravesical instillations of chemotherapy and biological preparations. Chemotherapy combinations, most often gemcitabine combination with mitomycin C or docetaxel, recorded RFS rates equal to or lower than 35% after two years [The bladder cancer treatment scenario has significantly evolved over time, since it not only encompasses traditional approaches, such as surgery and chemotherapy, but also immunotherapy integration. BCG immunotherapy has been applied to prevent NMIBC relapse and progression for more than four decades. However, recent improvements in scientists’ understanding about this topic have opened new room to enhance its anti-tumor effectiveness. Alongside BCG, the introduction of immune checkpoint inhibitors has revolutionized the standard care provided to patients with metastatic bladder cancer, as well as expanded their potential use in BCG-unresponsive NMIBC cases. These immune checkpoint inhibitors, such as anti-PD1 or anti-PD-L1 agents, have garnered increasing interest within the bladder cancer-related scientific community. Critical considerations comprise whether using immune checkpoint inhibitors can delay or change patients’ need of undergoing surgery and potentially affect their outcome, as well as whether toxicity is proportional to NMIBC severity.Pembrolizumab (an anti-PD1 agent) has recently received FDA approval to be applied to high-risk BCG-unresponsive NMIBC patients with and without concomitant CIS who are not suitable candidates for cystectomy. This approval was based on findings resulting from the ongoing phase 2 KEYNOTE-057 study, which achieved a three-month CR rate of 40.6% and a median RD of 16.2 months after more than two years of follow-up with 96 patients. In total, 46.2% of all 39 patients who achieved CR presented RD equal to or longer than 12 months [According to the phase 2 SWOG S1605 monotherapy study conducted with 74 CIS patients treated with atezolizumab (anti-PD-L1 agent), CR rates reached 41.1% at three months and 26.0% at six months [Vicinium (oportuzumab monatox) is a fusion protein composed of an epithelial cell adhesion molecule-specific antibody fragment and Pseudomonas exotoxin. It exerts its antitumor effects by inhibiting protein synthesis [Intravesical gene therapy is a promising alternative to treat NMIBC, given the bladder’s suitability for such a treatment. Nadofaragene firadenovec, which is a gene-mediated intravesical therapy based on using human IFN-α2b, recorded a CR rate of 53.4% at three months in a phase 3 study conducted with CIS patients—24.3% of them remained free from high-grade relapse after one year [OncoTheradThese promising preclinical effectiveness findings have encouraged our research team to perform a clinical-veterinary trial with dogs diagnosed with naturally occurring bladder cancer. Dogs participating in this trial were treated with intravesical (44 mg/mL) and intramuscular (22 mg/mL) OncoTheradAnother prospective multicenter clinical-veterinary study was conducted with 19 dogs diagnosed with recurrent oral melanoma who had previously undergone at least one course of first-line chemotherapy [The current study recorded a pCR rate of 72.7% (95% CI) and a mean RFS of 21.4 months. The mean response duration among all 32 patients with pCR was 14.3 months. No patient progressed to muscle-invasive or metastatic disease during treatment. Altogether, these findings have emphasized the highly promising antitumor effects of OncoTheradBCG toxicity can be classified into two categories: local and systemic side effects. Local side effects are more prevalent but, oftentimes, less severe. Sometimes, they can lead to treatment discontinuation [Similarly, studies did not identify significant differences in systemic side effects between non-maintenance and maintenance therapy groups [Adverse effects observed for pembrolizumab used as a monotherapy were assessed in a cohort of 102 patients. Results have shown that 97.1% of patients experienced at least one adverse event, 65.7% of them had treatment-related adverse events, and 29.4% of the investigated population experienced grade 3–5 adverse events [With respect to OncoTheradPrevious studies conducted by our research team have evidenced this nanocompound’s low toxicity in vitro in grade II urinary bladder carcinoma cells (5637 cell line), as well as 75% cell viability, and suggested that neoplastic cell death induced by OncoTheradBriefly, the current study has shown that OncoTheradThe immune microenvironment of the urinary bladder has unique features. On the one hand, the bladder uses several non-specific defense mechanisms to remain free from infections [Nowadays, TLR agonists are acknowledged as effective immune stimulants with significant potential to be used in immunotherapy applied to different tumor types, including bladder cancer. One of the immune mechanisms accounting for both detecting and controlling tumor cell proliferation lies in TLR4-mediated production of inflammatory cytokines in macrophages [The non-canonical TLR4 signaling pathway plays a pivotal role in triggering interferon (IFN) production. IFNs have strong antitumor effects since they enable TNF-related apoptosis-inducing ligand (TRAIL) generation. TRAIL is known for its ability to induce cell death in tumor cells [The current study has shown that OncoTheradThe TLR4-mediated interferon signaling pathway activation induced by OncoTheradThe role played by TLRs in enhancing humoral immune responses, as well as in affecting B cells both directly and indirectly through their interactions with other immune cells, has been increasingly acknowledged. B cells themselves express TLRs. Moreover, they undergo polyclonal stimulation when they are exposed to TLR ligands such as OncoTheradAlthough TLRs’ influence on triggering humoral immune responses is well-documented for helper T cells and for the intrinsic activation of B cells, the general understanding concerning the potential consequences of TLR ligands in LFs and follicular dendritic cells remains limited. Consequently, the current study has emphasized the notable influence of the TLR4 signaling pathway activation induced by (MRB-CFI-1) on LFs’ development and arrangement processes. This OncoTheradIdentifying blood-based biomarkers capable of reflecting dynamic changes in the tumor microenvironment and of predicting tumor responses to immunotherapies is a promising path for enhancing current treatment strategies [Our study has certain limitations that should be acknowledged. Firstly, the relatively small sample size may not provide a precise reflection of the safety and efficacy of OncoTheradMoreover, our single-arm study was constrained by the absence of a direct comparator group. Nevertheless, it’s worth emphasizing that there are limited effective treatment alternatives available beyond radical cystectomy for this patient population. Additionally, comparing our findings with off-label treatments is a complex endeavor due to historical inconsistencies in defining adequate BCG therapy, variations in BCG dosing regimens, the inherent heterogeneity of patient populations, and differences in monitoring or surveillance protocols.In recognition of these limitations, our research group is actively pursuing further investigations to substantiate the safety and efficacy of OncoTherad