scholarly journals New and Emerging Therapies in the Management of Bladder Cancer

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1146
Author(s):  
Chelsea K. Osterman ◽  
Matthew I. Milowsky
Keyword(s):  
Bladder Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Rapid Evolution ◽  
New Agents ◽  
Drug Conjugates ◽  
Emerging Therapies ◽  
Improved Outcomes ◽  
Selection For

The treatment landscape for bladder cancer has undergone a rapid evolution in the past five years with the approval of seven new agents. New classes of medications have improved outcomes for many patients who previously had limited treatment options, but there is still much to learn about how to optimize patient selection for these agents and the role of combination therapies. The aims of this review are to discuss these newly approved agents for bladder cancer and to feature promising drugs and combinations—including immune checkpoint inhibitors, targeted therapies, and antibody–drug conjugates—that are in development.

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

2021 ◽  
Author(s):  
Kirollos S Hanna ◽  
Samantha Larson ◽  
Jenny Nguyen ◽  
Jenna Boudreau ◽  
Jennifer Bulin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Second Line ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Advanced Bladder Cancer ◽  
Checkpoint Inhibitor Therapy ◽  
Antibody Drug

Abstract Disclaimer In an effort to expedite the publication of articles pandemic, 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. Purpose 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. Summary 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. Conclusion 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.

scholarly journals Mechanisms of immune evasion in bladder cancer

2019 ◽  
Vol 69 (1) ◽  
pp. 3-14 ◽  
Author(s):  
Paul L. Crispen ◽  
Sergei Kusmartsev
Keyword(s):  
Immune Response ◽  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Immune Evasion ◽  
Cancer Biology ◽  
Checkpoint Inhibitors ◽  
New Agents ◽  
Multiple Trials ◽  
Checkpoint Inhibitor Therapy

AbstractWith the introduction of multiple new agents, the role of immunotherapy is rapidly expanding across all malignancies. Bladder cancer is known to be immunogenic and is responsive to immunotherapy including intravesical BCG and immune checkpoint inhibitors. Multiple trials have addressed the role of checkpoint inhibitors in advanced bladder cancer, including atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab (all targeting the PD1/PD-L1 pathway). While these trials have demonstrated promising results and improvements over existing therapies, less than half of patients with advanced disease demonstrate clinical benefit from checkpoint inhibitor therapy. Recent breakthroughs in cancer biology and immunology have led to an improved understanding of the influence of the tumor microenvironment on the host’s immune system. It appears that tumors promote the formation of highly immunosuppressive microenvironments preventing generation of effective anti-tumor immune response through multiple mechanisms. Therefore, reconditioning of the tumor microenvironment and restoration of the competent immune response is essential for achieving optimal efficacy of cancer immunotherapy. In this review, we aim to discuss the major mechanisms of immune evasion in bladder cancer and highlight novel pathways and molecular targets that may help to attenuate tumor-induced immune tolerance, overcome resistance to immunotherapy and improve clinical outcomes.

scholarly journals Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Vanessa Wookey ◽  
Axel Grothey
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Multiple Cancer ◽  
Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

scholarly journals Immunotherapy in Adrenocortical Carcinoma: Predictors of Response, Efficacy, Safety, and Mechanisms of Resistance

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 304
Author(s):  
Marta Araujo-Castro ◽  
Eider Pascual-Corrales ◽  
Javier Molina-Cerrillo ◽  
Teresa Alonso-Gordoa
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Mechanisms Of Resistance ◽  
Response Efficacy ◽  
Predictors Of Response ◽  
Primary Endpoints ◽  
Tumor Mutational Burden

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with limited treatment options in the advanced stages. Immunotherapy offers hope for altering the orthodox management of cancer, and its role in advanced ACC has been investigated in different studies. With the aim clarifying the role of immunotherapy in ACC we performed a comprehensive review about this topic focusing on the predictors of response, efficacy, safety, and the mechanisms of resistance. Five clinical trials with four immune checkpoint inhibitors (pembrolizumab, avelumab, nivolumab, and ipilimumab) have investigated the role of immunotherapy in advanced ACC. Despite, the different primary endpoints used in these studies, the reported rates of overall response rate and progression free survival were generally poor. Three main potential markers of response to immunotherapy in ACC have been described: Expression of PD-1 and PD-L1, microsatellite instability and tumor mutational burden. However, none of them has been validated in prospective studies. Several mechanisms of ACC immunoevasion may be responsible of immunotherapy failure, and a greater knowledge of these mechanisms might lead to the development of new strategies to overcome the immunotherapy resistance. In conclusion, although currently the role of immunotherapy is limited, the identification of immunological markers of response and the implementation of strategies to avoid immunotherapy resistance could improve the efficacy of this therapy.

Pharmacotherapy review: Emerging treatment modalities in transthyretin cardiac amyloidosis

2021 ◽  
Author(s):  
Emily Plumadore ◽  
Lindsay Lombardo ◽  
Katherine P Cabral
Keyword(s):  
Treatment Options ◽  
Disease State ◽  
Treatment Modalities ◽  
Limited Data ◽  
Limited Evidence ◽  
Agent Selection ◽  
Selection For ◽  
Tea Extract

Abstract Disclaimer 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. Purpose This review aims to summarize the evidence and pharmacological characteristics of treatment options for transthyretin amyloid cardiomyopathy (ATTR-CM). Additionally, this review highlights the role of clinical pharmacists in helping to secure newly introduced therapies. Summary ATTR-CM, a disease characterized by misfolded protein that is deposited in the myocardium and disrupts cardiac functioning, has historically been underdiagnosed due to the need for invasive biopsy and an illusion of rarity. Once diagnosed, limited treatment modalities for ATTR-CM have led providers to rely on nonpharmacological remedies or off-label use of medications with limited evidence of benefit. However, recent noninvasive diagnostic advancements and heightened disease state awareness have revealed increased prevalence of ATTR-CM. This has led to the introduction of several first-in-class pharmaceuticals with actions targeted at inhibiting the various phases of amyloidosis: TTR stabilizers include diflunisal and first-in-class, Food and Drug Administration (FDA)-approved tafamidis; TTR silencers include patisiran and inotersen; fibril disrupters include doxycycline with tauroursodeoxycholic acid; and alternative agents include green tea extract and curcumin. Conclusion ATTR-CM treatments have emerged and, despite current limited data, are continuing to evolve. Tafamidis, the only agent approved by FDA for ATTR-CM, shows promise to improve survival and quality of life in patients with ATTR-CM. Pharmacists can play a key role in assisting with agent selection for this disease state, as well as providing knowledge about current and future clinical trials evaluating the safety and efficacy of the available treatment modalities.

The Role of Immune Checkpoint Inhibitors in Bladder Cancer

2021 ◽  
pp. 435-443
Author(s):  
Sanchia S. Goonewardene ◽  
Karen Ventii ◽  
Amit Bahl ◽  
Raj Persad ◽  
Hanif Motiwala ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors

scholarly journals The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Marina Degoricija ◽  
Jelena Korac-Prlic ◽  
Katarina Vilovic ◽  
Tonci Ivanisevic ◽  
Benedikt Haupt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Inflammatory Response ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Locally Advanced ◽  
Histopathological Analysis ◽  
Tumor Escape ◽  
Induced Tumors ◽  
Frequent Mutations ◽  
Muscle Invasive

Abstract Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

scholarly journals Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1449 ◽  
Author(s):  
Veronica Mollica ◽  
Alessandro Rizzo ◽  
Rodolfo Montironi ◽  
Liang Cheng ◽  
Francesca Giunchi ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Urothelial Carcinoma ◽  
Checkpoint Inhibitors ◽  
Cancer Control ◽  
Parp Inhibitors ◽  
Published Data ◽  
Drug Conjugates ◽  
Platinum Based Chemotherapy ◽  
Metastatic Urothelial Carcinoma

Urothelial carcinoma (UC) is a frequent cause of cancer-related deaths worldwide. Metastatic UC has been historically associated with poor prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate of 18%. Although platinum-based chemotherapy remains the mainstay of medical treatment for patients with metastatic UC, chemotherapy clinical trials produced modest benefit with short-lived, disappointing responses. In recent years, the better understanding of the role of immune system in cancer control has led to the development and approval of several immunotherapeutic approaches in UC therapy, where immune checkpoint inhibitors have been revolutionizing the treatment of metastatic UC. Because of a better tumor molecular profiling, FGFR inhibitors, PARP inhibitors, anti-HER2 agents, and antibody drug conjugates targeting Nectin-4 are also emerging as new therapeutic options. Moreover, a wide number of trials is ongoing with the aim to evaluate several other alterations and pathways as new potential targets in metastatic UC. In this review, we will discuss the recent advances and highlight future directions of the medical treatment of UC, with a particular focus on recently published data and ongoing active and recruiting trials.

scholarly journals Treatment Options for Carbapenem-resistant Gram-negative Bacterial Infections

2019 ◽  
Vol 69 (Supplement_7) ◽  
pp. S565-S575 ◽  
Author(s):  
Yohei Doi
Keyword(s):  
Bacterial Infections ◽  
Treatment Options ◽  
Clinical Development ◽  
Gram Negative Bacteria ◽  
First Line ◽  
Safe Alternative ◽  
New Agents ◽  
Gram Negative ◽  
Carbapenem Resistant

AbstractAntimicrobial resistance has become one of the greatest threats to public health, with rising resistance to carbapenems being a particular concern due to the lack of effective and safe alternative treatment options. Carbapenem-resistant gram-negative bacteria of clinical relevance include the Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, and more recently, Stenotrophomonas maltophilia. Colistin and tigecycline have been used as first-line agents for the treatment of infections caused by these pathogens; however, there are uncertainties regarding their efficacy even when used in combination with other agents. More recently, several new agents with activity against certain carbapenem-resistant pathogens have been approved for clinical use or are reaching late-stage clinical development. They include ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, plazomicin, eravacycline, and cefiderocol. In addition, fosfomycin has been redeveloped in a new intravenous formulation. Data regarding the clinical efficacy of these new agents specific to infections caused by carbapenem-resistant pathogens are slowly emerging and appear to generally favor newer agents over previous best available therapy. As more treatment options become widely available for carbapenem-resistant gram-negative infections, the role of antimicrobial stewardship will become crucial in ensuring appropriate and rationale use of these new agents.

Integrating Genomics Into Neuro-Oncology Clinical Trials and Practice

2018 ◽  
pp. 148-157
Author(s):  
Evanthia Galanis ◽  
Farhad Nassiri ◽  
Shannon Coy ◽  
Romina Nejad ◽  
Gelareh Zadeh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Options ◽  
Rapid Evolution ◽  
Cns Tumors ◽  
World Health ◽  
World Health Organization Classification ◽  
Improved Outcomes ◽  
Oncology Clinical Trials ◽  
Health Organization

Important advances in our understanding of the molecular biology of brain tumors have resulted in a rapid evolution in the taxonomy of central nervous system (CNS) tumors, which culminated in the revised 2016 World Health Organization classification of CNS tumors that incorporates an integrated molecular/histologic diagnostic approach. Our expanding understanding of brain tumor genomics and molecular evolution during the disease course has started to impact clinical management. Furthermore, incorporation of genomic information in ongoing and planned neuro-oncology clinical trials is expected to lead to improved outcomes and result in personalized treatment options for patients with CNS malignancies.

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