Treatment Of Advanced Bladder Cancer Research Articles

Advancements in First-Line Treatment of Metastatic Bladder Cancer: EV-302 and Checkmate-901 Insights and Future Directions.

Advanced bladder cancer patients have historically failed to achieve prolonged duration of response to conventional chemotherapy and needed better first-line treatment regimens. The approval of nivolumab in combination with gemcitabine and cisplatin and pembrolizumab with antibody-drug conjugate enfortumab vedotin has revolutionized the first-line treatment of advanced bladder cancer in many countries. In this review, we summarize the intricate differences between the two landmark clinical trials that led to their incorporation into the current standard of care for advanced bladder cancer. We further discuss newer novel treatment options in the second and subsequent lines of treatment on progression, like immunotherapy in combination with other agents, including fibroblast growth factors receptor inhibitors, human epidermal growth factor inhibitors, antibody-drug conjugates, tyrosine kinase inhibitors, and novel antibodies. Finally, we discuss the integration of these novel therapies into current clinical practice amidst the rapidly evolving landscape of advanced bladder cancer treatment, aiming to enhance patient outcomes.

Targeted and immunotherapy for the management of advanced urothelial carcinoma of the bladder.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The activity of targeted and immunotherapy for the management of advanced bladder cancer is reviewed. Platinum-based chemotherapy is standard first-line treatment for advanced bladder cancer. Pembrolizumab is approved alone as first-line therapy for patients who are ineligible for any platinum-based chemotherapy and with enfortumab for patients ineligible for cisplatin-based chemotherapy. Avelumab is approved for maintenance therapy in patients who have not progressed with first-line platinum-containing therapy. Pembrolizumab, avelumab, and nivolumab are approved second-line therapy in patients who experience progression during or after platinum-containing chemotherapy. Erdafitinib is indicated for advanced disease that has susceptible FGFR2 or FGFR3 genetic alterations and has progressed during or after treatment with at least one line of platinum-containing chemotherapy. Enfortumab vedotin and sacituzumab govitecan are antibody-drug conjugates. They are both approved for patients who have received anti-PD-L1 or anti-PD-1 therapy and treatment with platinum-containing chemotherapy. Enfortumab is also indicated for patients who are ineligible to receive cisplatin-based therapy and have received one or more prior lines of therapy. Six targeted and immunotherapeutic agents have been approved for patients with advanced urothelial bladder cancer. They all have demonstrated activity in patients for whom disease has progressed during or after platinum-based therapy. Pembrolizumab, with and without enfortumab, has demonstrated first-line activity, and avelumab is a key maintenance therapy after first-line treatment. The results of additional clinical trials should provide evidence to establish the exact role in therapy of each agent in patients with advanced disease.

Abstract 1916: Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid tumors

Abstract Century Therapeutics is developing a Nectin4-targeting IPSC-derived cell therapy for the treatment of Nectin4 expressing solid tumors. The Nectin proteins (Nectin1, Nectin2, Nectin3 and Nectin4) are members of the calcium independent immunoglobulin superfamily of cell adhesion molecules (CAMs) involved in adhesive processes that help in the growth and development of tissues. Nectin 1, 2 and 3 are normally found in adult tissue whereas Nectin4 is mainly found in normal placental and embryonic tissue. Nectin4 is also expressed in different types of cancer including urothelial, ovarian, lung and head/neck cancers. Nectin4 is established as a biomarker for worse prognosis in cancers and is linked with carcinogenesis and disease severity. These features establish Nectin4 as a promising target for anti-tumor drug development. Enfortumab vedotin, an antibody drug conjugate targeting Nectin4 positive tumors, has demonstrated benefit in clinical trials and is FDA approved for treatment of advanced bladder cancer. We have identified novel single-domain antibodies (VHH) that bind to multiple epitopes on Nectin4 extracellular domain. The VHH antibodies were engineered into chimeric antigen receptor (CAR) formats and characterized for expression, cell activation through antigen engagement, and cytotoxicity activity in primary T-cells. Selected binders demonstrated efficacy in multiple CAR formats in primary T-cells in a mouse xenograft model using OVCar-3 tumor cells. The lead CARs engineered into primary T-cells demonstrated tumor inhibition similar to a reference CAR using the ASG-5ME antibody (Enfortumab) as the Nectin4 binder. The CARs were engineered into our IPSC-derived iNK and iT cells and demonstrated cytotoxicity activity against a panel of cell lines with a range of cell surface expression of Nectin4. Based on these studies, Century Therapeutics is advancing the lead Nectin4 binder for development of an IPSC-derived cell therapy to treat Nectin4 positive solid tumors. Citation Format: Jill M. Carton, Chris Dower, Michael Miller, John Wheeler, Sean Heron, Hillary J. Millar, David Walker, Daniel J. Perry, Andriana Lebid, Luis Cocka, Dae Hwan Kim, Barry Morse, Buddha Gurung, Maisha Harris, Annalise Jethon, Michael Naso, Hy Levitsky. Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1916.

Activity of antibody-drug conjugates (ADCs) with radiation in preclinical bladder cancer models.

664 Background: Antibody-drug conjugates (ADCs) are a novel class of therapeutics that combine a tumor cell targeting antibody with a cytotoxic payload. Two ADCs are currently approved in the US for treatment of advanced bladder cancer: enfortumab vedotin (EV) and sacituzumab govitecan (SG). Radiation therapy (RT) plays a central role in trimodality therapy (TMT), a curative treatment approach for muscle-invasive bladder cancer (MIBC). However, the biological activity of ADCs combined with RT in preclinical MIBC models has not been reported. Methods: We use a molecularly annotated panel of human MIBC preclinical models to test the impact of RT on expression of ADC targets and define the combined activity of EV and SG with RT. We also test the in vivo activity of combining ADCs with image-guided, fractionated RT in bladder cancer flank xenograft mouse models. Results: Radiation has variable impact on expression levels of nectin-4 and trop-2, the targets of EV and SG, respectively, as determined by immunoblot, immunofluorescence microscopy, and immunohistochemistry (IHC). Whereas modest dose-dependent increases in nectin-4 and/or trop-2 levels were observed in some models, no significant changes were observed in other models. Importantly, RT did not lead to a significant decrease in nectin-4 or trop-2 expression in any of the models. EV and SG showed additive or synergistic cell killing when combined with RT across preclinical models in vitro. Combining EV or SG with fractionated RT in vivo was well-tolerated, showed improved tumor control, and prolonged survival in bladder cancer flank xenograft mouse models compared to either ADC or RT alone. Conclusions: ADCs demonstrate combination activity with RT across a panel of molecularly diverse bladder cancer preclinical models. These studies provide preclinical data supporting clinical trials to investigate the safety and efficacy of combining ADCs with RT as a bladder-preserving therapy for MIBC.

Sialidase NEU3 Contributes to the Invasiveness of Bladder Cancer.

Bladder cancer is the 10th most commonly diagnosed cancer worldwide. The current standard treatment for advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. However, the response rate to chemotherapy is only 50%, owing to cisplatin resistance, and there is a need for novel therapies. Because the invasiveness of bladder cancer greatly influences patient prognosis, a mechanistic analysis of the invasive function can lead to therapeutic targets. Sialidases, which remove sialic acid residues from the nonreducing ends of sugar chains and catalyze the initial reaction in the degradation of sugar chains, are predicted to be involved in cell invasion and motility. However, the involvement of sialidases in bladder cancer, especially their relationship with the invasive ability, remains unclear. Here, using patient tissues and multiple bladder cancer cell lines, we show that the sialidase NEU3 is highly expressed in bladder cancer. Analysis of NEU3's function using its siRNA-mediated knockdown revealed that NEU3 contributes to bladder cancer invasiveness. Mechanistic analysis showed that NEU3 activates ERK and PI3K signaling. Our results show that NEU3 is involved in the malignancy of bladder cancer, and its suppression may lead to novel treatments for bladder cancer.

G3BP1 and SLU7 Jointly Promote Immune Evasion by Downregulating MHC-I via PI3K/Akt Activation in Bladder Cancer.

Immune checkpoint inhibitors (ICIs) show promise as second-line treatment for advanced bladder cancer (BLCA); however, their responsiveness is limited by the immune evasion mechanisms in tumor cells. This study conduct a Cox regression analysis to screen mRNA-binding proteins and reveals an association between Ras GTPase-activating protein-binding protein 1 (G3BP1) and diminished effectiveness of ICI therapy in patients with advanced BLCA. Subsequent investigation demonstrates that G3BP1 enhances immune evasion in BLCA cells by downregulating major histocompatibility complex class I (MHC-I) through phosphoinositide 3-kinase (PI3K)/Akt signaling activation. Mechanistically, G3BP1 interacts with splicing factor synergistic lethal with U5 snRNA 7 (SLU7) to form a complex with poly(A)-binding protein cytoplasmic 1 and eukaryotic translation initiation factor 4 gamma 1. This complex stabilizes the closed-loop structure of the mRNAs of class IA PI3Ks and consequently facilitates their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC-I. Consistently, targeting G3BP1 with epigallocatechin gallate (EGCG) impedes immune evasion and sensitizes BLCA cells to anti-programmed cell death (PD)-1 antibodies in mice. Thus, G3BP1 and SLU7 collaboratively contribute to immune evasion in BLCA, indicating that EGCG is a precision therapeutic agent to enhance the effectiveness of anti-PD-1 therapy.

Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer

Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-β1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.

Immune checkpoint inhibitors therapy in advanced bladder carcinoma: A meta-analysis of phase III randomized controlled trials.

e16584 Background: Currently, platinum-based chemotherapy is the standard treatment for advanced bladder cancer. Immune checkpoint inhibitors (ICIs) have been evaluated in these patients with clinical trials. There is no meta-analysis available of phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in these patients. In this article, we write about the meta-analysis of ICIs use in advanced bladder cancer. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google scholar, and ClinicalTrials.gov were searched for relevant studies with prespecified terms. We included only phase III randomized controlled trials comparing immune checkpoint inhibitors therapy versus chemotherapy/placebo in patients with advanced bladder carcinoma. Outcomes studied were Overall survival (OS), Progression-free survival (PFS), Objective response rate (ORR), and Grade 3 or higher adverse events (AE). We used a random effects model via RevMan 5.4 software to perform the meta-analysis. Results: 8 phase III RCTs met the inclusion criteria with a total of 5041 patients (immune checkpoint inhibitors = 2481 patients, Chemotherapy/placebo = 2560 patients) and a median follow-up of 24 months. Compared to the chemotherapy/placebo group, immune checkpoint inhibitors showed higher OS [HR = 0.83 (0.73-0.93) P = 0.002]. No significant differences were observed in PFS [HR = 0.84(0.68-1.05) P = 0.13] and ORR [HR = 2.15(0.51-9.09) P = 0.30] between the two groups. Compared to the chemotherapy group, immune checkpoint inhibitors showed significantly fewer severe adverse events [HR = 0.21 (0.14-0.32) P < 0.00001]. Conclusions: The use of immune checkpoint inhibitors in patients with advanced bladder carcinoma is associated with favorable overall survival and fewer severe adverse events. The two groups observed no significant differences between progression-free survival and objective response rates.

Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor.

Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

Abstract 1678: Overcoming treatment resistance in advanced bladder cancers using a neo-adjuvant combination with a natural product analog

Abstract Urinary bladder cancer (BC) is a common cancer worldwide, with approximately 573,278 new cases and 212,536 deaths arising annually. Tumors detected beyond the transitional zone of the bladder (advanced BC) account for most deaths. In advanced BC, tumor heterogeneity and resistance to successive chemotherapy regimens are major contributors to morbidity and mortality. Toxicity associated with the combination of Gemcitabine and Cisplatin (G+C) treatment limits the efficacy of chemotherapy. We tested the potential antitumor activity of a novel combination therapy involving a semisynthetic derivative of the pentacyclic triterpene (PTA) Ursolic Acid (N-methyl piperazine conjugated Ursolate, UA4) and Gemcitabine (Gem) in two Gem resistant BC cell lines developed in the laboratory. UA4 was synthesized from the PTA Ursolic Acid and Gem was purchased from LC-Labs. We tested the response to Gem and UA4 on naïve (WT) and Gem Resistant (GemR) cells. We generated Gem resistant BC cell lines HTB-4 (T24) and HTB-9 (5637) by repeated selection in increased Gem doses in vitro. The surviving cells were tested for a stable resistant phenotype. We measured the sensitivity to Gem and UA4 alone, and in adjuvant and neo-adjuvant combinations by colorimetric, cell counting, or clonogenic assays. The antitumor efficacy of UA4 and Gem were tested in vivo by xenograft studies on Fox N1-/- athymic mice (both sexes). The expression of markers associated with drug resistance was determined by qPCR, immunoblotting, and immunofluorescence studies. The 50% growth inhibition (IC50) dose in Gem treated cells increased significantly in 5637 and T24 GemR cells - 10-fold higher in GemR (100nM) than in WT cells (10 nM). Both WT and GemR cells showed equal sensitivity to UA4 (~5 µM). GemR cells showed elevated mRNA expression of a pyrimidine salvaging enzyme, cytidine deaminase (CDA), which degrades intracellular Gem, MRP2, and ENT1, all related to limiting intracellular drug availability. Tetrahydrouridine (THU), a competitive inhibitor of CDA, reduced the resistance significantly, indicating CDA as the principal mediator of resistance in GemR cells. Oral administration of UA4 was highly effective in reducing tumor growth of 5637 WT and GemR xenografts, whereas Gem (25mg/kg, 2x per week, i.p.) did not significantly reduce growth of GemR xenografts. Gem antitumor activity on 5637 WT tumors was predominantly due to apoptosis. Increased expression of autophagy markers, but not markers of apoptosis, was evident in vitro and in vivo treatments with UA4. Overall, treatment with UA4 was equally effective in decreasing viability in both WT and GemR advanced BC cells in vitro and reducing their tumor growth in vivo. Unlike Gem, UA4 did not induce significant levels of apoptosis but mainly autophagy-induced cell death. Ongoing studies indicate potential to use UA4 as an adjuvant or neo-adjuvant therapy in the treatment of advanced BC. Citation Format: Juliette R. Seremak, Sunilkanth Bonigala, Kunj B. Gupta, Siva S. Panda, Bal L. Lokeshwar. Overcoming treatment resistance in advanced bladder cancers using a neo-adjuvant combination with a natural product analog [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1678.

Patient and Caregiver Perceptions of Advanced Bladder Cancer Systemic Treatments: Infodemiology Study Based on Social Media Data.

In 2022, it was estimated that more than 80,000 new cases of bladder cancer (BC) were diagnosed in the United States, 12% of which were locally advanced or metastatic BC (advanced BC). These forms of cancer are aggressive and have a poor prognosis, with a 5-year survival rate of 7.7% for metastatic BC. Despite recent therapeutic advances for advanced BC, little is known about patient and caregiver perceptions of different systemic treatments. To further explore this topic, social media can be used to collect the perceptions of patients and caregivers when they discuss their experiences on forums and online communities. The aim of this study was to assess patient and caregiver perceptions of chemotherapy and immunotherapy for treating advanced BC from social media-posted data. Public posts on social media in the United States between January 2015 and April 2021 from patients with advanced BC and their caregivers were collected. The posts included in this analysis were geolocalized to the United States; collected from publicly available domains and sites, including social media sites such as Twitter and forums such as patient association forums; and were written in English. Posts mentioning any line of chemotherapy or immunotherapy were qualitatively analyzed by two researchers to classify perceptions of treatments (positive, negative, mixed, or without perception). A total of 80 posts by 69 patients and 142 posts by 127 caregivers mentioning chemotherapy, and 42 posts by 31 patients and 35 posts by 32 caregivers mentioning immunotherapy were included for analysis. These posts were retrieved from 39 public social media sites. Among patients with advanced BC and their caregivers, treatment perceptions of chemotherapy were more negative (36%) than positive (7%). Most of the patients' posts (71%) mentioned chemotherapy factually without expressing a perception of the treatment. The caregivers' perceptions of treatment were negative in 44%, mixed in 8%, and positive in 7% of posts. In combined patient and caregiver posts, immunotherapy was perceived positively in 47% of posts and negatively in 22% of posts. Caregivers also posted more negative perceptions (37%) of immunotherapy than patients (9%). Negative perceptions of both chemotherapy and immunotherapy were mainly due to side effects and perceived lack of effectiveness. Despite chemotherapy being standard first-line therapy for advanced BC, negative perceptions were identified on social media, particularly among caregivers. Addressing these negative perceptions of treatment may improve treatment adoption. Strengthening support for patients receiving chemotherapy and their caregivers to help them manage side effects and understand the role of chemotherapy in the treatment of advanced BC would potentially enable a more positive experience.

Magnetic Resonance Diffusion-Weighted Imaging to Evaluate the Clinical Efficacy of CalliSpheres Drug-Loaded Microspheres in the Treatment of Advanced Bladder Cancer

The MR diffusion-weighted imaging technique was used to evaluate the efficacy and safety of CalliSpheres drug-loaded microspheres for transarterial chemoembolization in the treatment of advanced bladder cancer. 35 patients with advanced bladder cancer were treated with CalliSpheres DLMS for transarterial chemoembolization. Imaging techniques such as magnetic resonance (MR) diffusion-weighted imaging were used to evaluate the therapeutic effect. The changes in serum tumor markers, immune function indexes, and oxidative stress indexes in patients before and after treatment were compared, and the quality of life of patients and the incidence of adverse reactions during follow-up were also evaluated. The results showed that the overall response rate (ORR) was 74.29% and that the disease control rate (DCR) was 97.14%. Compared with that before treatment, the ADC value of the tumor in patients with advanced bladder cancer detected by MR diffusion-weighted imaging technology was significantly increased after treatment and the maximum tumor diameter was significantly decreased P < 0.05 . Compared with those before treatment, the levels of serum tumor markers (CA199, CA724, and CA125) in advanced bladder cancer patients after treatment decreased P < 0.05 . The levels of T-lymphocyte subsets (CD3+ and CD4+) decreased, and CD8+ levels increased P < 0.05 . The levels of superoxide dismutase decreased P > 0.05 . At the same time, the subscale evaluation of function, symptoms, quality of life, adverse reactions, and economics of patients with advanced bladder cancer on the QLQ-C30 scale improved after treatment, and the incidence rate and recurrence rate during the follow-up period were 8.57% and 11.43%, respectively. It showed that CalliSpheres DLMS had a good clinical effect and high safety in the treatment of advanced bladder cancer and was a safe and feasible treatment method. The use of MR diffusion-weighted imaging technology could achieve quantitative evaluation of clinical efficacy of advanced bladder cancer.

Immune status for monitoring and treatment of bladder cancer.

The high recurrence rate of non-muscle invasive bladder cancer (BC) and poor prognosis of advanced BC are therapeutic challenges that need to be solved. Bacillus Calmette-Guerin (BCG) perfusion was the pioneer immunotherapy for early BC, and the discovery of immune checkpoint inhibitors has created a new chapter in the treatment of advanced BC. The benefit of immunotherapy is highly anticipated, but its effectiveness still needs to be improved. In this review, we collated and analysed the currently available information and explored the mechaisms by which the internal immune imbalance of BC leads to tumour progression. The relationship between immunity and progression and the prognosis of BC has been explored through tests using body fluids such as blood and urine. These analytical tests have attempted to identify specific immuyne cells and cytokines to predict treatment outcomes and recurrence. The diversity and proportion of immune and matrix cells in BC determine the heterogeneity and immune status of tumours. The role and classification of immune cells have also been redefined, e.g., CD4 cells having recognised cytotoxicity in BC. Type 2 immunity, including that mediated by M2 macrophages, Th2 cells, and interleukin (IL)-13, plays an important role in the recurrence and progression of BC. Pathological fibrosis, activated by type 2 immunity and cancer cells, enhances the rate of cancer progression and irreversibility. Elucidating the immune status of BC and clarifying the mechanisms of action of different cells in the tumour microenvironment is the research direction to be explored in the future.

Novel immunotherapy in the management of advanced urothelial cancer - review of the literature

Bladder neoplasms, with the most common urothelial carcinoma, are responsible for approximately 200,000 deaths annually, which is 2.1% of the total cancer deaths in 2018. Recent decades have brought a steadily growing share of this cancer in the statistics. The 5-year survival rate is 77.1% for the United States and it varies depending on the stage of the diagnosed neoplasm, from 96% for cancer in situ to only 5% for the disseminated form with distant metastases. The treatment of urothelial cancer can be divided depending on the stage and advancement. Three main categories of bladder cancer can be distinguished: non-muscle invasive bladder cancer, treated by surgical approaches, and muscle-invasive bladder cancer, treated with chemotherapeutics, lastly advanced bladder cancer with distant metastases, treated with intensive chemotherapy in the MVAC scheme (methotrexate, vinblastine, doxorubicin, and cisplatin). Recently introduced checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma by increasing patient life expectancy, progression-free survival, and durability of clinical response. This review of the literature will discuss the use of immunotherapy in the treatment of advanced bladder cancer.

Three-Dimensional Conformal Radiotherapy Combined with Gemcitabine and Docetaxel in the Treatment of Advanced Bladder Cancer and Its Effects on Inflammatory Factors and Immune Function.

Objective To assess the efficacy of three-dimensional conformal radiotherapy (3D-CRT) combined with GT chemotherapy (gemcitabine+docetaxel) in the treatment of advanced bladder cancer and its influence on inflammatory factors and immune function. Methods A total of 42 elderly patients with advanced bladder cancer who were admitted to our hospital from January 2019 to January 2020 were included and assigned to the GT group (21 cases) receiving GT chemotherapy and combination group (21 cases) given 3D-CRT combined with GT chemotherapy. The clinical efficacy, immune function, inflammatory factors, tumor markers, urinary angiogenesis molecules before and after treatment, 1-year survival rate, 2-year survival rate, and incidence of adverse reactions of the two groups were compared. SPSS 22.0 statistical software was used for data processing and analysis. Results The combination group had 5 cases of CR, 12 cases of PR, 3 cases of SD, and 1 case of PD, with an ORR of 80.95% (17/21), which was remarkably higher than the ORR of 57.14% (12/21) in the GT group which had 3 cases of CR, 9 cases of PR, 5 cases of SD, and 4 cases of PD (P < 0.05). The 1-year survival rate of the combination group was 76.19% (16/21), and the 2-year survival rate was 47.62% (10/21), which were higher than the 1-year survival rate of 47.62% (10/21) and 2-year survival rate of 19.05% (4/21) in the GT group (P < 0.05). The two groups presented similar results in terms of adverse reactions rate (P > 0.05). After treatment, the combination group obtained significantly lower levels of urinary bladder cancer antigen (UBC), nuclear matrix protein-22 (NMP-22), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) than the GT group (P < 0.05). The CD3+, CD4+, and CD4+/CD8+ levels of the two groups of patients were lower than those before treatment (P < 0.05), but no statistical difference was observed between the two groups after treatment (P > 0.05). The levels of interleukin-6 (IL-6) and interferon-γ (IFN-γ) of the two groups witnessed a decline after treatment, with lower results in the combination group as compared to the control group (P < 0.05). Before treatment, no significant difference in the Generic Quality of Life Inventory-74 (GQOLI-74) score between the two groups was found (P > 0.05). After treatment, the combination group had higher GQOLI-74 scores than the GT group (P < 0.05). Conclusion 3D-CRT combined with GT chemotherapy yields a significant effect on the treatment of elderly advanced bladder cancer by effectively protecting immune function, mitigating inflammation, inhibiting tumor marker levels and the expression of angiogenic molecules, and improving patients' survival.

New Directions and Challenges in Targeted Therapies of Advanced Bladder Cancer: The Role of FGFR Inhibitors.

Simple SummaryThe aim of this study was to present and analyze the up-to-date literature describing the epidemiology, genetics, and histopathology of bladder cancer, as well as the latest methods of bladder cancer treatment. The treatment of urothelial cancer was divided depending on its stage and advancement. FGFR3 mutations and overexpression occur more frequently in bladder cancer than any other malignancy, occurring in nearly 80% of the tumors. Closer acknowledgement of targeted therapy will help physicians to navigate specific groups of patients for whom this treatment strategy can be beneficial. To that end, intense clinical research was conducted, bringing evidence for effectiveness and safety of FGFR inhibitors. Recent years of research have truly set a positive perspective for the better understanding of the complex issue of urothelial carcinoma pathology and management.Bladder neoplasms, including the most common urothelial carcinoma, have been an escalating problem for years, especially in highly developed countries. Recent decades have brought us a steadily growing share of this cancer in terms of both morbidity and mortality statistics. Bladder neoplasms are not only a therapeutic challenge but also an economical one due to the demanding, costly diagnostics and treatment. The treatment of urothelial cancer can be divided depending on the stage and advancement; thus, we can distinguish three main categories: non-muscle invasive bladder cancer, conventionally treated by surgical interventions; muscle invasive bladder cancer, conventionally treated with chemotherapeutics; and advanced bladder cancer with distant metastases, conventionally treated with the intensive chemotherapy in the MVAC scheme (methotrexate, vinblastine, doxorubicin, and cisplatin). Recent years have brought a breakthrough: immunotherapy and targeted therapy were discovered to be beneficial for patients disqualified from chemotherapy or patients who progressed despite treatment. This literature review summarizes the latest research into the use of targeted therapy in the treatment of advanced bladder cancer, its benefits, and its limitations.

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer.

The treatment landscape of advanced bladder cancer continues to evolve with novel therapeutics approved in recent years and many in the pipeline. Here we review the role of the novel agents enfortumab vedotin and sacituzumab govitecan in treatment of advanced disease. Patients with advanced bladder cancer often first receive platinum-based therapy, while immune checkpoint inhibitors offer a maintenance option following cytotoxic chemotherapy or a second-line option. Despite various first- and second-line options, patients with significant comorbidities and treatment-related adverse events will experience disease progression requiring alternative treatment. Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates approved in patients with advanced bladder cancer following platinum-based and immune checkpoint inhibitor therapy. Following platinum-based therapy and immunotherapy in patients with advanced bladder cancer, enfortumab vedotin, targeting Nectin-4, improves overall survival while sacituzumab govitecan, targeting Trop-2, is associated with a 27% response rate. With these new approaches to disease management, however, it remains critical to understand safety, efficacy, and operational considerations to optimize outcomes. When selecting an antibody-drug conjugate to treat patients with bladder cancer, it is important to note the adverse event profile of each agent to optimize outcomes and safety for patients.

RAF1 amplification: an exemplar of MAPK pathway activation in urothelial carcinoma.

Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

Progress in treatment of PD-1/PD-L1 inhibitors for bladder cancer

Because of the limited effect of traditional treatment methods such as surgical treatment, radiotherapy and chemotherapy,the emergence of immunotherapy has brought new hope for the treatment of patients with bladder cancer. As an immune checkpoint inhibitor, programmed death receptor 1/programmed death receptor-ligand 1 (PD-1/PD-L1) inhibitor has shown good anti-tumor activity and safety in the treatment of advanced bladder cancer, and has been recommended for advanced bladder cancer as second-line treatment by NCCN guidelines. PD-1/PD-L1 inhibitor for the treatment of bladder cancer has covered the first-line and second-line treatment, as well as maintenance therapy after first-line chemotherapy of locally advanced or metastatic bladder cancer, adjuvant and neoadjuvant therapy of muscle-invasive bladder cancer, treatment of high-risk non-muscle invasive bladder cancer failed by Bacille Calmette-Guérin vaccine perfusion, and bladder preservation therapy of muscle-invasive bladder cancer. Some of related studies have achieved certain results, and some are in progress, both of which need to be further examined. Maybe it can provide new guidance and ideas for clinical treatment of bladder cancer.