Adaptive Immunity in Genitourinary Cancers.

CONTEXT: While urothelial and renal cell cancers have exhibited modest responses to novel immune checkpoint inhibitors targeting the programmed death ligand 1 and its receptor, response rates in patients with prostate cancer have remained poor. The factors underlying suboptimal outcomes observed in patients treated with novel immunotherapies are still to be resolved. OBJECTIVE: To review the literature and describe the key adaptive immune physiological events associated with cancer progression and therapeutic response in genitourinary (GU) cancers. EVIDENCE ACQUISITION: We performed a nonsystematic, collaborative narrative review to highlight recent advancements leading to the current state of knowledge on the critical mediators of antitumor adaptive immunity to GU cancers. Further, we discuss the findings on the pre- and post-treatment immunological events that either are unique to each of the three cancer types or exhibit overlapping clinical associations. EVIDENCE SYNTHESIS: Aging-associated immune function decline is a major factor underlying poor outcomes observed in patients treated with both conventional and novel immunotherapies. Other cancer immunobiological aspects associated with suboptimal responses in GU cancers include the overall tumor mutational burden, mutations in specific tumor suppressor/DNA damage repair genes (KDM6A, PTEN, STAG2, TP53, ATM, and BRCA2), and abundance of multiple functional states of adaptive immune cells and their spatiotemporal localization within the tumor immune microenvironment. Understanding these mechanisms may potentially lead to the development of prognostic and predictive biomarkers such as immune cell infiltration profiles and tertiary lymphoid structures (TLSs) that associate with variable clinical outcomes depending on the nature of the novel immunotherapeutic approach. Implementation of newer immune-monitoring technologies and improved preclinical modeling systems will augment our understanding of the host and tumor intrinsic factors contributing to the variability of responses to immunotherapies. CONCLUSIONS: Despite the tremendous progress made in the understanding of dynamic and static adaptive immune elements within the tumor immune landscape, several knowledge gaps remain. A comprehensive knowledge thus gained will lead to precision immunotherapy, improved drug sequencing, and a therapeutic response. PATIENT SUMMARY: We performed a collaborative review by a diverse group of experts in the field to examine our understanding of the events and crosstalk between cancer cells and the patient's immune system that are associated with responses to novel immunotherapies. An evolving understanding of tumor-intrinsic and host-related immune alterations, both before and after therapy, will aid in the discovery of promising markers of responses to immunotherapy as well as the development of unique therapeutic approaches for the management of genitourinary cancers.

The impact of biological sex on diseases of the urinary tract.

Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.

Bladder cancer, inflammageing and microbiomes.

Ageing is correlated with elevated bladder cancer incidence, morbidity and mortality. Advanced age is also associated with elevated markers of chronic inflammation and perturbations in gut and urinary tract microbiota. One reason for the increased incidence and mortality of bladder cancer in the elderly might be that age-associated changes in multiple microbiomes induce systemic metabolic changes that contribute to immune dysregulation with potentially tumorigenic effects. The gut and urinary microbiomes could be dysregulated in bladder cancer, although the effect of these changes is poorly understood. Each of these domains - the immune system, gut microbiome and urinary microbiome - might also influence the response of patients with bladder cancer to treatment. Improved understanding of age-related alterations to the immune system and gut and urinary microbiomes could provide possible insight into the risk of bladder cancer development and progression in the elderly. In patients with bladder cancer, improved understanding of microbiota might also provide potential targets for therapeutic intervention.

Functionally distinct resident macrophage subsets differentially shape responses to infection in the bladder.

Resident macrophages are abundant in the bladder, playing key roles in immunity to uropathogens. Yet, whether they are heterogeneous, where they come from, and how they respond to infection remain largely unknown. We identified two macrophage subsets in mouse bladders, MacM in muscle and MacL in the lamina propria, each with distinct protein expression and transcriptomes. Using a urinary tract infection model, we validated our transcriptomic analyses, finding that MacM macrophages phagocytosed more bacteria and polarized to an anti-inflammatory profile, whereas MacL macrophages died rapidly during infection. During resolution, monocyte-derived cells contributed to tissue-resident macrophage pools and both subsets acquired transcriptional profiles distinct from naïve macrophages. Macrophage depletion resulted in the induction of a type 1-biased immune response to a second urinary tract infection, improving bacterial clearance. Our study uncovers the biology of resident macrophages and their responses to an exceedingly common infection in a largely overlooked organ, the bladder.

Sex Differences in Bladder Cancer Immunobiology and Outcomes: A Collaborative Review with Implications for Treatment.

CONTEXT: Urothelial carcinoma of the bladder (UCB) exhibits significant sexual dimorphism in the incidence, etiology, and response to intravesical immunotherapy. Environmental factors such as tobacco use and clinical management issues such as delayed presentation have widely been associated with sex differences in UCB outcomes. Emerging findings from immune checkpoint blockade trials are suggestive of differential outcomes in females compared with males. Sex-specific differences in the way immune system functions and responds to pathogenic insults are well established. As such, an in-depth understanding of the genetic and epigenetic factors contributing to sex-associated differences in response to immunomodulatory therapies is needed urgently for improved management of UCB. OBJECTIVE: To review the associations between patient sex and clinical outcomes, with a focus on the incidence, host intrinsic features, and response to therapies in UCB. EVIDENCE ACQUISITION: Using the PubMed database, this narrative review evaluates published findings from mouse model-based and clinical cohort studies to identify factors associated with sex and clinical outcomes in bladder cancer. A scoping review of the key findings on epidemiology, genetic, hormonal, immune physiology, and clinical outcomes was performed to explore potential factors that could have implications in immunomodulatory therapy design. EVIDENCE SYNTHESIS: Sex-associated differences in UCB incidence and clinical outcomes are influenced by sex hormones, local bladder resident immune populations, tumor genetics, and bladder microbiome. In the context of therapeutic outcomes, sex differences are prominent in response to bacillus Calmette-Guérin immunotherapy used in the treatment of non-muscle-invasive bladder cancer. Similarly, with respect to tumor molecular profiles in muscle-invasive bladder cancer, tumors from females show enrichment of the basal subtype. CONCLUSIONS: Among proposed tumor/host intrinsic factors that may influence response to immune-based therapies, patient sex remains a challenging consideration that deserves further attention. Evidence to date supports a multifactorial origin of sexual dimorphism in the incidence and outcomes of UCB. PATIENT SUMMARY: In this review, we highlight the sex-associated host and tumor intrinsic features that may potentially drive differential disease progression and therapeutic response in urothelial carcinoma of the bladder.

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches.

With the mechanistic understanding of immune checkpoints and success in checkpoint blockade using antibodies for the treatment of certain cancers, immunotherapy has become one of the hottest areas in cancer research, with promise of long-lasting therapeutic effect. Currently, however, only a proportion of cancers have a good response to checkpoint inhibition immunotherapy. Better understanding of the cancer response and resistance mechanisms is essential to fully explore the potential of immunotherapy to cure the majority of cancers. Bladder cancer, one of the most common and aggressive malignant diseases, has been successfully treated both at early and advanced stages by different immunotherapeutic approaches, bacillus Calmette-Guérin (BCG) intravesical instillation and anti-PD-1/PD-L1 immune checkpoint blockade, respectively. Therefore, it provides a good model to investigate cancer immune response mechanisms and to improve the efficiency of immunotherapy. Here, we review bladder cancer immunotherapy with equal weight on BCG and anti-PD-1/PD-L1 therapies and demonstrate why and how bladder cancer can be used as a model to study the predictors and mechanisms of cancer immune response and shine light on further development of immunotherapy approaches and response predictive biomarkers to improve immunotherapy of bladder cancer and other malignancies. We review the success of BCG and anti-PD-1/PD-L1 treatment of bladder cancer, the underlying mechanisms and the therapeutic response predictors, including the limits to our knowledge. We then highlight briefly the adaptation of immunotherapy approaches and predictors developed in other cancers for bladder cancer therapy. Finally, we explore the potential of using bladder cancer as a model to investigate cancer immune response mechanisms and new therapeutic approaches, which may be translated into immunotherapy of other human cancers. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The Microbiome and Genitourinary Cancer: A Collaborative Review.

CONTEXT: The recent discovery of the existence of a human genitourinary microbiome has led to the investigation of its role in mediating the pathogenesis of genitourinary malignancies, including bladder, kidney, and prostate cancers. Furthermore, although it is largely recognized that members of the gastrointestinal microbiota are actively involved in drug metabolism, new studies demonstrate additional roles and the potential necessity of the gastrointestinal microbiota in dictating cancer treatment response. OBJECTIVE: To summarize the current evidence of a mechanistic role for the genitourinary and gastrointestinal microbiome in genitourinary cancer initiation and treatment response. EVIDENCE ACQUISITION: We conducted a literature search up to October 2018. Search terms included microbiome, microbiota, urinary microbiome, bladder cancer, urothelial carcinoma, renal cell carcinoma, kidney cancer, testicular cancer, and prostate cancer. EVIDENCE SYNTHESIS: There is preliminary evidence to implicate the members of the genitourinary microbiota as causative factors or cofactors in genitourinary malignancy. Likewise, the current evidence for gastrointestinal microbes in dictating cancer treatment response is mainly correlative; however, we provide examples where therapeutic agents used for the treatment of genitourinary cancers are affected by the human-associated microbiota, or vice versa. Clinical trials, such as fecal microbiota transplant to increase the efficacy of immunotherapy, are currently underway. CONCLUSIONS: The role of the microbiome in genitourinary cancer is an emerging field that merits further studies. Translating microbiome research into clinical action will require incorporation of microbiome surveillance into ongoing and future clinical trials as well as expansion of studies to include metagenomic sequencing and metabolomics. PATIENT SUMMARY: This review covers recent evidence that microbial populations that reside in the genitourinary tract-and were previously not known to exist-may influence the development of genitourinary malignancies including bladder, kidney, and prostate cancers. Furthermore, microbial populations that exist at sites outside of the genitourinary tract, such as those that reside in our gut, may influence cancer development and/or treatment response.

Building on a Solid Foundation: Enhancing Bacillus Calmette-Guérin Therapy.

CONTEXT: More than 40 yr ago, bacillus Calmette-Guérin (BCG) was introduced as an adjuvant therapy following transurethral resection of papillary tumours and as a treatment for carcinoma in situ of the bladder. Some 30 yr after its introduction, BCG maintenance therapy was found to be superior to induction therapy alone, representing the most relevant clinical improvement to BCG therapy since its inception. OBJECTIVE: To review current efforts and future opportunities to improve BCG immunotherapy. EVIDENCE ACQUISITION: English online databases (eg, PubMed and clinicaltrials.gov) were searched for clinical trials and meta-analyses of BCG therapy for bladder cancer. The information retrieved was reviewed and sel ected by all the authors and, while representative of the field, is not necessarily exhaustive. EVIDENCE SYNTHESIS: Current knowledge supports the notion that careful patient management from diagnosis to therapy may contribute positively to outcome following BCG immunotherapy. In the future, patient evaluation using predictive immunological or molecular biomarkers will help in identifying those most likely to benefit from BCG therapy. Trials assessing immune modulators in combination with BCG or the use of recombinant BCG are ongoing and results will be forthcoming in the near future. CONCLUSIONS: Enhancing BCG to improve patient outcomes is the responsibility of treating physicians and researchers. Future efforts will continue to improve how non-muscle-invasive urothelial carcinoma is evaluated, treated, and ultimately cured. PATIENT SUMMARY: Bacillus Calmette-Guérin (BCG) immunotherapy to prevent the recurrence and progression of urothelial carcinoma is invasive and demanding for patients. Meticulous diagnostics, correct application of BCG, and selection of patients likely to respond to therapy will ensure that the highest benefit can be attained from this therapy. Current research is focused on discovering biomarkers to identify patients most likely to benefit from BCG immunotherapy. Biomarker identification, new immune modulators, and genetically modified BCG strains are undergoing clinical trial testing to improve outcomes for bladder cancer patients.

Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer.

The Fourth Annual Albert Institute Bladder Cancer Care and Research Symposium was held from September 14th-16th in Houston, Texas. The symposium covered a range of topics relevant to bladder cancer, including basic science aspects of immunology and immunotherapy that inform clinical management; intravesical therapy for non-muscle invasive disease; understanding the nuances of carcinoma in situ; and optimizing patient care and outcomes following therapy. The moving landscape of bladder cancer from an industry perspective was also discussed. In the following sections we discuss intrinsic and extrinsic factors, including the immune microenvironment and sex bias, in the context of bladder cancer; how these influence tumor development, progression, and treatment strategies; and how the interpretation of immune features in relation to molecular subtypes informs both treatment decisions and response. We conclude with a summary of key points that will need to be addressed to ensure best use of new knowledge in this area for improved clinical management of patients with bladder cancer.

Biology of nonmuscle-invasive bladder cancer: pathology, genomic implications, and immunology.

PURPOSE OF REVIEW: Despite that nearly 75% of bladder cancer patients are diagnosed with nonmuscle-invasive disease, our understanding of the biological landscape in bladder cancer is primarily within the context of muscle-invasive bladder cancer. More recent studies addressing the genomic changes and immunology of nonmuscle-invasive bladder cancer (NMIBC) have helped to extend our understanding of this prevalent disease. RECENT FINDINGS: Genomic studies reveal that NMIBC possesses complexity that can be defined by specific gene expression signatures and has helped to define subsets within this disease. These subsets possess different risk profiles that may impact treatment decisions. In addition, the baseline or posttreatment immunological response to the growing tumor may help to inform whether a specific NMIBC subset is likely to progress. SUMMARY: Findings from studies addressing the molecular landscape of NMIBC may help to establish parameters for stratifying patient risk within this disease as well as establish novel or targeted treatment strategies. Inclusion of information about the immune response within tumors will likely contribute to defining the relative risk and treatment strategy for these patients.

Mechanisms of BCG immunotherapy and its outlook for bladder cancer.

BCG immunotherapy is the gold-standard treatment for non-muscle-invasive bladder cancer at high risk of recurrence or progression. Preclinical and clinical studies have revealed that a robust inflammatory response to BCG involves several steps: attachment of BCG; internalization of BCG into resident immune cells, normal cells, and tumour urothelial cells; BCG-mediated induction of innate immunity, which is orchestrated by a cellular and cytokine milieu; and BCG-mediated initiation of tumour-specific immunity. As an added layer of complexity, variation between clinical BCG strains might influence development of tumour immunity. However, more than 40 years after the first use of BCG for bladder cancer, many questions regarding its mechanism of action remain unanswered. Clearly, a better understanding of the mechanisms underlying BCG-mediated tumour immunity could lead to improved efficacy, increased tolerance of treatment, and identification of novel immune-based therapies. Indeed, enthusiasm for bladder cancer immunotherapy, and the possibility of combining BCG with other therapies, is increasing owing to the availability of targeted immunotherapies, including checkpoint inhibitors. Understanding of the mechanism of action of BCG immunotherapy has advanced greatly, but many questions remain, and further basic and clinical research efforts are needed to develop new treatment strategies for patients with bladder cancer.

Limited Macrophage Positional Dynamics in Progressing or Regressing Murine Atherosclerotic Plaques-Brief Report.

Objective- Macrophages play important roles in the pathogenesis of atherosclerosis, but their dynamics within plaques remain obscure. We aimed to quantify macrophage positional dynamics within progressing and regressing atherosclerotic plaques. Approach and Results- In a stable intravital preparation, large asymmetrical foamy macrophages in the intima of carotid artery plaques were sessile, but smaller rounded cells nearer plaque margins, possibly newly recruited monocytes, mobilized laterally along plaque borders. Thus, to test macrophage dynamics in plaques over a longer period of time in progressing and regressing disease, we quantified displacement of nondegradable phagocytic particles within macrophages for up to 6 weeks. In progressing plaques, macrophage-associated particles appeared to mobilize to deeper layers in plaque, whereas in regressing plaques, the label was persistently located near the lumen. By measuring the distance of the particles from the floor of the plaque, we discovered that particles remained at the same distance from the floor regardless of plaque progression or regression. The apparent deeper penetration of labeled cells in progressing conditions could be attributed to monocyte recruitment that generated new superficial layers of macrophages over the labeled phagocytes. Conclusions- Although there may be individual exceptions, as a population, newly differentiated macrophages fail to penetrate significantly deeper than the limited depth they reside on initial entry, regardless of plaque progression, or regression. These limited dynamics may prevent macrophages from escaping areas with unfavorable conditions (such as hypoxia) and pose a challenge for newly recruited macrophages to clear debris through efferocytosis deep within plaque.

Bladder resident macrophages: Mucosal sentinels.

Macrophages are instrumental in the response to infectious and noninfectious diseases, however, their role in the bladder is poorly understood. Indeed, the bladder is a mucosal tissue frequently overlooked in research, despite the prevalence of illnesses such as urinary tract infection and bladder cancer. Notably, bladder tissue macrophages are among the most populous resident immune cells in this organ and recent studies support that resident macrophages and infiltrating monocytes play nonredundant roles in response to infection, immunotherapy, and inflammation. Advancing our understanding of macrophage behavior in the bladder is complicated by the difficulty in obtaining tissue-resident cells. Surmounting this challenge, however, for a greater understanding of macrophage ontology, impact on innate and adaptive immunity, and regulation of homeostasis, will ultimately contribute to better therapies for common afflictions of the bladder.

Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review.

CONTEXT: Bacillus Calmette-Guérin (BCG) is currently the most effective intravesical therapy for nonmuscle invasive bladder cancer, reducing not only recurrence rates but also preventing progression and reducing deaths. However, response rates to BCG vary widely and are dependent on a multitude of factors. OBJECTIVE: To review existing data on clinical, pathologic, immune, and molecular markers that allow prediction of BCG response. EVIDENCE ACQUISITION: PubMed and MEDLINE search of English language literature was conducted from its inception to July 2017 using appropriate search terms. Following systematic literature review and analysis of data, consensus voting was used to generate the content of this review. EVIDENCE SYNTHESIS: As seen in the EORTC and CUETO risk nomograms, clinicopathologic features, especially tumor stage and grade, are the most effective predictors of BCG response. Data are less robust with regards to the association of response with age, female sex, recurrent tumors, multiplicity of tumors, and the presence of carcinoma in situ. Single biomarkers, such as tumor p53 and urinary interleukin-2 expression, have had limited success in predicting BCG response, possibly due to the multifaceted nature of the generated immune response. More comprehensive biomarker panels (eg, urinary cytokines), have a more robust correlation with response, as do patterns of urinary cytologic fluorescent in-situ hybridization examination. Gene expression data correlate with disease progression, but studies examining potential associations with BCG response are limited. CONCLUSIONS: Currently, the best predictors of BCG response are clinicopathologic features such as tumor grade and stage. Panels of urinary cytokines, as well as fluorescent in-situ hybridization patterns of cytologic anomalies, appear to be promising biomarkers. The complexity of the immune response to BCG and the heterogeneity of bladder cancer suggest that future studies should amalgamate measures reflecting innate immune response and tumor/stromal gene expression before these can be adopted for clinical use. PATIENT SUMMARY: Bacillus Calmette-Guérin (BCG) immunotherapy is an effective treatment for many patients with nonmuscle invasive bladder cancer. An individual's response to BCG can be predicted by using various features of the cancer. In the future, predictive markers using molecular measures of the tumor type and the immune response to BCG may allow us to precisely know an individual's likely outcome after BCG treatment.

Urinary Tract Infection in a Small Animal Model: Transurethral Catheterization of Male and Female Mice.

Urinary tract infections (UTI) are extremely common worldwide, incurring significant morbidity and healthcare-associated expenses. Small animal models, which accurately reflect disease establishment and progression, permit dissection of host-pathogen interactions and generation of immunity to infection. In mice, intravesical instillation of uropathogenic E. coli, the causative agent in more than 85% of community acquired UTI, recapitulates many of the stages of infection observed in humans. Until recently, however, UTI could only be modeled in female animals. This limitation has hindered the study of sex-related differences in UTI, as well as other bladder pathologies, such as cancer. Here, we describe a method to instill male mice that allows direct comparison between female and male animals and provide a detailed protocol to assess bladder tissue by flow cytometry as a means to better understand host responses to infection. Together, these approaches will aid in the identification of host factors that contribute to sex biases observed in UTI and other bladder-associated diseases.

Enterococcus faecalis Promotes Innate Immune Suppression and Polymicrobial Catheter-Associated Urinary Tract Infection.

Enterococcus faecalis, a member of the human gastrointestinal microbiota, is an opportunistic pathogen associated with hospital-acquired wound, bloodstream, and urinary tract infections. E. faecalis can subvert or evade immune-mediated clearance, although the mechanisms are poorly understood. In this study, we examined E. faecalis-mediated subversion of macrophage activation. We observed that E. faecalis actively prevents NF-κB signaling in mouse RAW264.7 macrophages in the presence of Toll-like receptor agonists and during polymicrobial infection with Escherichia coliE. faecalis and E. coli coinfection in a mouse model of catheter-associated urinary tract infection (CAUTI) resulted in a suppressed macrophage transcriptional response in the bladder compared to that with E. coli infection alone. Finally, we demonstrated that coinoculation of E. faecalis with a commensal strain of E. coli into catheterized bladders significantly augmented E. coli CAUTI. Taken together, these results support the hypothesis that E. faecalis suppression of NF-κB-driven responses in macrophages promotes polymicrobial CAUTI pathogenesis, especially during coinfection with less virulent or commensal E. coli strains.

Proceedings of the 3rd Annual Albert Institute for Bladder Cancer Research Symposium.

The Third Annual Albert Institute Bladder Symposium was held on September 8-10th, 2016, in Denver Colorado. Participants discussed several critical topics in the field of bladder cancer: 1) Best practices for tissue analysis and use to optimize correlative studies, 2) Modeling bladder cancer to facilitate understanding and innovation, 3) Targeted therapies for bladder cancer, 4) Tumor phylogeny in bladder cancer, 5) New Innovations in bladder cancer diagnostics. Our understanding of and approach to treating urothelial carcinoma is undergoing rapid advancement. Preclinical models of bladder cancer have been leveraged to increase our basic and mechanistic understanding of the disease. With the approval of immune checkpoint inhibitors for the treatment of advanced urothelial carcinoma, the treatment approach for these patients has quickly changed. In this light, molecularly-defined subtypes of bladder cancer and appropriate pre-clinical models are now essential to the further advancement and appropriate application of these therapeutic improvements. The optimal collection and processing of clinical urothelial carcinoma tissues samples will also be critical in the development of predictive biomarkers for therapeutic selection. Technological advances in other areas including optimal imaging technologies and micro/nanotechnologies are being applied to bladder cancer, especially in the localized setting, and hold the potential for translational impact in the treatment of bladder cancer patients. Taken together, advances in several basic science and clinical areas are now converging in bladder cancer. These developments hold the promise of shaping and improving the clinical care of those with the disease.

Measurement of Dipeptidylpeptidase Activity in vitro and in vivo.

Dipeptidylpeptidases (DPPs) are serine proteases, which cleave small proteins and peptides possessing a proline or an alanine in the second position of their N-terminus. Among the members of this family, dipeptidylpeptidase 4 (DPP4) is constitutively expressed in the extracellular space. DPP4 is found at the surface of many hematopoietic and non-hematopoietic cells and is also present in many biological fluids in a bioactive soluble form. DPP4 expression is modulated by inflammation, and measurements of its activity have been used as biomarker for disease. Here, we describe a method to evaluate the enzymatic activity of DPP4 in vitro and in vivo.

Innovation in Bladder Cancer Immunotherapy.

Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease. Finally, we explore immunotherapeutic strategies, which have been demonstrated to be successful in the treatment of other malignancies, for their potential to treat and cure patients with nonmuscle and muscle invasive bladder cancer.