Immunogene Therapy Using Interferon
Immunogene therapy refers to the delivery of genetic material for the purpose of modulating a host immune response. In immunogene therapy, tumor-induced immunosuppression can be altered, and antigen-specific antitumor responses can be stimulated. Therapies such as high-dose IL-2 have been used effectively in treating renal cell carcinoma, albeit with significant systemic adverse events. Interferon- belongs to the family of cytokine proteins and works to pleiotropically impede tumor cell growth. IFN has been demonstrated to augment the response of T helper type 1 immune responses when combined with BCG, and as such its use as combination therapy with BCG has been explored in several trials. In a national multi-institutional phase II trial evaluate the combination of IFN and BCG in patients with non-muscle invasive disease, 59% of BCG-naïve and 45% of prior BCG unresponsive patients remained disease free at 24-months.37 A hypothetical way to potentiate the immunogene effect of IFN may be to deliver it within a gene therapy/adenoviral construct, ideally increasing transfection rate of IFN into urothelial cells and stimulating an immune response by virtue of the adenovirus vehicle itself . Unlike the delivery of systemic cytokines such as IL-2 therapy, intravesically delivered IFN has been established as well tolerated by patients and is likely well tolerated even through gene therapy.
Understanding The Genomics Of Non
Advances in whole genome sequencing technology have vastly improved our insights into the complexity and heterogeneity of bladder cancer. In particular, parallel efforts to comprehensively characterize the molecular composition of muscle-invasive disease have revealed that MIBC can be broadly grouped into basal and luminal subtypes that are similar to those found in breast cancer, with distinct clinical features.1214 Efforts to similarly characterize NMIBC have also been undertaken, with mutations identified in the TERT promoter,15 FGFR3,1618 PIK3CA,19 and STAG220. Hurst and colleagues described two genomic subtypes for stage Ta tumors one group was characterized by no detectable copy-number alterations, while the second group was defined by a loss of chromosome 9q.21
Bcg Strains: Is There A Difference
There have been several strains of BCG developed since the original strain in 1921, but whether these strains have varying efficacies on bladder tumours remain unclear. While hundreds of thousands of patients have been treated with BCG for prevention of NMIBC, no clinical difference has been shown among studies despite the use of various strains worldwide.
Trials using various strains have consistently demonstrated the efficacy of BCG immunotherapy in reducing recurrence and progression of NMBIC in all countries across the globe. BCG is recommended by all scientific associations from the European Association of Urology , American Urological Association, Japanese Association or the Canadian Urological Association.
Sengiku and colleagues demonstrated no significant difference between the studied strains . Supporting a previous European Organization for Research and Treatment of Cancer meta-analysis which suggested that there is no large difference between different strains , a recent meta-analysis of randomised trials performed by Quan et al concluded that no meaningful correlations between BCG strain and other survival outcomes could be drawn. Another systematic review and meta-analysis by Chou et al concluded that no comment can be made regarding differences among strains. Gan et al studied the effects of substrain differences in BCG immunotherapy for bladder cancer and came to a similar conclusion.
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Efficacy Of Intravesical Treatment In Immunological Disorders
With the possibility that BCG may exhibit a systemic immune response, future research may be warranted regarding the use of BCG in the fight against viruses such as SARS-CoV-2 and various immunological disorders. There has been promising research in recent years exploring the use of BCG against viruses and other immunological disorders with which to build from and guide future studies. Additionally, new clinical trials are being planned to explore the efficacy of boosting immune responses with BCG in the fight against COVID-19.
Recently, a study published in 2019 by Gofrit et al. followed 1371 patients for 1 year after their diagnosis with bladder cancer. During follow-up, 65 patients developed Alzheimers disease , a condition in which the immune system is a major contributor to pathogenesis. Of the patients who developed AD, 21 were treated with intravesical BCG, while 44 did not receive BCG therapy. It was determined that patients treated with intravesical BCG manifested more than 4-fold less risk for AD than those not treated with intravesical BCG.
Catheterizable Continent Diversion Pouch
This is a reservoir of bowel with a stoma that is catheterizable for emptying the bladder. The urine is siphoned out of the urinary reservoir with a small catheter every four to six hours. The catheterizable pouch may require surgical repair at some point after surgery due to the wear and tear of frequent catheterization. This type of reconstruction is not performed on patients with a history of bowel disease.
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What Type Of Chemotherapy Is Used For Bladder Cancer
Cisplatin-based chemotherapy has been the best standard treatment for bladder cancer since the 1970s. Based on the results of clinical trials from the 1990s, the two regimens most commonly used are dose-dense MVAC and GC. Chemotherapy goes into the body through a vein. It may be infused with a catheter into a vein or through a port that is placed under the skin, usually in the right side of the chest.
MVAC uses four drugs: methotrexate , vinblastine , doxorubicin , and cisplatin . We no have effective anti-nausea medication and injections that can keep immune systems from being depleted by chemotherapy. This has have improved our ability to give MVAC safely on an accelerated dose-dense schedule. The National Comprehensive Cancer Network now recommends MVAC be given according to the dose-dense or DD schedule due to improved toxicity and suggested improvement in efficacy compared with the standard schedule. Click here to view the NCCN Guidelines.
A clinical trial conducted in the late 1990s showed that the combination of gemcitabine , plus cisplatin , gives similar anticancer effects to standard MVAC combination. Both GC and DD MVAC have been useful in bladder cancer in delaying recurrence, extending life and sometimes achieving a cure, and both regimens are routinely used in the neoadjuvant and metastatic settings. Clinical trials are underway to assess whether the addition of another agent to these regimens improves outcomes.
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Importance Of The Quality Of Life
The bladder cancer literature focuses on CSS and OS, providing almost no information on patients quality of life and function, which is often of greatest importance for the elderly community. Patients treated with RC, experience significant changes in urinary and sexual functions, accompanied with psychological and relationship stresses. Integrity and body image has also shown to be significantly affected . Furthermore, elderly patients are less likely to undergo neobladder reconstruction because of the higher peri-operative morbidity and mortality risks of the complex procedure, and due to the relatively high probability of functional problems requiring long-term increased care and potentially compromising the patients independence and social life. Patients older than 75 years old, treated with orthotopic neobladder were reported to have daytime and nighttime continence of only 56 and 25%, respectively, which is worse than younger populations .
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Intravesical Treatmentrelated Adverse Events And Risk For Ards
With knowledge of the recent SARS-CoV-2 pandemic, and the risk for severe complications such as ARDS, it is necessary to review the side effects of intravesical treatment in an attempt to determine its safety in COVID-19 and immunocompromised patients. One major drawback of intravesical BCG is that it is associated with more side effects when compared with intravesical chemotherapy, though more serious adverse outcomes are encountered in less than 5% of patients. Though still debated, pulmonary complications appear to be of two categories: hypersensitivity reactions and mycobacterial pneumonia. An interstitial pattern on chest radiography, lymphocytosis on bronchial alveolar lavage and absence of granulomas on lung biopsy, as well as negative sputum and tissue cultures, are indicative of hypersensitivity response. Mycobacterial pneumonia is characterized by biopsies revealing granulomata and radiographic evidence of consolidation, although testing for acid-fast bacteria may be negative. A large analysis of 2602 patients treated with intravesical BCG revealed 0.4% of patients developed life-threatening BCG sepsis, and 0.7% developed granulomatous pneumonitis.
With regard to other intravesical therapy, MMC has little systemic absorption due to low molecular weight, and chemical cystitis is common.
Box : Recommendations For Intravesical Bcg
RCTs and practice pattern research demonstrate that BCG immunotherapy in NMIBC reduces recurrences and progression, and affects mortality
3-week BCG maintenance is confirmed to reduce recurrence rates compared with induction alone, as well as metastasis and mortality compared with maintenance chemotherapy thus, it is the optimal regimen for current practice
BCG maintenance schedules other than the 3-week schedule show no significant benefit in RCTs
In the period of around 1.52 years after the identification of high-grade NMIBC, nonradical alternative treatments for patients experiencing BCG-failure can be explored
After the first BCG failure, patients have several treatment options, including repeated BCG , BCG plus interferon, single-agent intravesical chemotherapy , sequential chemotherapy or device-assisted chemotherapy
After the second BCG failure, or if the disease is BCG-refractory, radical cystectomy should be considered with alternatives considered a matter of investigation by clinical trials
Patients with BCG-refractory disease who are not candidates for cystectomy can be considered for chemoradiation
Abbreviations: NMIBC, non-muscle-invasive bladder cancer RCTs, randomized controlled trials.
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Cancer Gene Therapy Backed By Blackstone Gets Trial Win
A gene therapy for bladder cancer that recently received $400 million in support from the private equity company Blackstone Group helped more than half of treated patients with resistant disease achieve remission.
The therapy, called nadofaragene firadenovec, was discovered by a Finnish-based research institute and first entered clinical study in 2012. The data revealed today at the Society of Urologic Oncology meeting came from a Phase 3 trial that is part of the agents Biologics License Application now before the FDA.
Licensed by its original owner, FKD Therapies Oy, to Switzerland-based Ferring Pharmaceuticals, nadofaragene firadenovec is now in the hands of the U.S. subsidiary FerGene. That company was created with the Blackstone investment and an additonal $170 million from Ferring. FerGene will commercialize the gene therapy in the U.S., with Ferring holding rights elsewhere.
Nadofaragene firadenovec is an an adenovirus-based gene therapy encoding production of the immunity-stimulating protein interferon alfa-2b. Viral vectors containing the gene are administered by catheter once every three months into the bladder, where they are absorbed into cells in the organs walls and begin stimulating interferon.
The clinical trial enrolled 157 patients with bladder cancer that has not spread to muscle walls and has stopped responding to treatment with Bacillus Calmette-Guérin vaccine.
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Questions To Ask The Health Care Team
After you learn about your treatment options and your general health, you might need more information. Consider asking your health care team the following:
Is my cancer curable?
What is my chance of recovery?
What are all of my treatment options?
What is the goal of each treatment?
What treatment do you recommend? Why?
How does this treatment help me?
What are some risks and potential side effects of this treatment?
Will I need to be in the hospital for treatment? Or can I stay home and come to the hospital or clinic during the day?
How long will each treatment last?
How will this treatment affect my daily life? Will I be able to perform my usual activities?
If I am worried about managing the costs related to my cancer care, who can help me with these concerns?
How can I keep myself as healthy as possible during treatment?
If I have questions or problems, who should I call?
What support services are available to my family?
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Description Of The Condition
Urothelial carcinoma of the bladder is the sixth most common cancer in men and the 19th most common cancer in women . It is estimated that the agestandardised incidence rate is 5.3 per 100,000 and mortality rate is 1.9 per 100,000 for both sexes . Based on their prognostic risk, people with urothelial bladder cancer can be broadly categorised into those with nonmuscle invasive bladder cancer and those with muscle invasive bladder cancer . People with NMIBC are at risk for recurrence of the tumour as well as progression to MIBC, which is associated with the risk of lymphatic and vascular metastatic spread and portends a markedly worse prognosis. Approximately 75% of people with bladder cancer have NMIBC at the time of diagnosis . NMIBC can be localised either to the mucosa or to the submucosa . Important risk factors for NMIBC are incorporated in the European Organisation for Research and Treatment of Cancer scoring system, which includes six clinical and pathological factors to predict short and longterm probabilities of recurrence and progression . Based on these parameters, people with NMIBC can be stratified into three risk groups using EORTC recurrence and progression parameters . CIS is a flat and noninvasive urothelial carcinoma however, people with CIS are at high risk of progression . Approximately 54% of these people progress to MIBC when no treatment is given .
Risk Adjusted Surveillance And Follow
Guideline Statement 32
32. After completion of the initial evaluation and treatment of a patient with NMIBC, a clinician should perform the first surveillance cystoscopy within three to four months.
The natural history of NMIBC is often characterized by recurrence, even for solitary, small, low-grade papillary tumors. At the time of first evaluation and treatment, none of the existent risk stratification tools or urinary biomarkers is sufficiently sensitive and specific to predict which patient will have an early tumor recurrence. Therefore, the only reliable way to know in a particular patient whether they are at risk for early recurrence is by cystoscopic visualization of the urothelium at a relatively early interval after the first treatment/resection. In addition, visualization at a relatively early interval allows the treating urologist to verify that the initial resection was complete. The Panel, therefore, felt that the first repeat cystoscopic evaluation should occur three to four months after the initial treatment and evaluation, regardless of the patient’s overall risk.
Guideline Statement 33
33. For a low-risk patient whose first surveillance cystoscopy is negative for tumor, a clinician should perform subsequent surveillance cystoscopy six to nine months later, and then annually thereafter surveillance after five years in the absence of recurrence should be based on shared-decision making between the patient and clinician.
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Patients 70 Years Or Older Undergoing Rc With Or Without Nac
Subsequent analysis was focused on patients 70 years or older who underwent RC . Of these patients, only 2643 received NAC. Patients receiving NAC were more likely to be aged 70 to 80 years . NAC was associated with higher median income and high school completion rate, CCI score of 0, higher clinical T stage, and treatment at an academic center or integrated network cancer program. Furthermore, PLND and robotic surgery were more common in the NAC cohort .
Patients receiving NAC had shorter LOS and were less likely to be readmitted within 30 days . They also had lower 30- and 90-day mortality . OS was improved with NAC .
When controlling for all other variables, NAC was a predictor of slightly lower LOS , as well as lower 30- and 90-day mortality . NAC was not associated with readmission rate. Notably, compared with the patients aged 70 to 80 years, patients 80 years had longer LOS , higher 30-day readmission rate , and higher 30- and 90-day mortality .
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Chemotherapy Before Surgery For Muscle
For muscle-invasive bladder cancer, our doctors may recommend chemotherapy before surgery. This treatment approach is called neoadjuvant chemotherapy. Large clinical studies have shown that this method improves cure rates and long-term survival for people with muscle-invasive bladder cancer. We typically use the drugs gemcitabine and cisplatin for neoadjuvant chemotherapy.
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Part I Current Status Of Intravesical Treatments
Immunomodulators Bacille Calmette-Guérin is the most adopted first-line immunotherapeutic and is the most effective treatment for prophylaxis and treatment of carcinoma in situ . Phase I and II trials have shown that other immunoregulators such as interferons , interleukin-2 , interleukin-12 , tumor necrosis factor , keyhole limpet hemocyanin and rubratin have activity in BCG-refractory patients, albeit with low durable remissions .
Chemotherapy Multiple chemotherapeutic agents, such as mitomycin C , doxorubicin , epirubicin , thiotepa , ethoglucid , valrubicin , cisplatin , gemcitabine , suramin or their combinations have been evaluated in patients meta-analyses did not show apparent superiority of a particular treatment. The addition of intravesical chemotherapy to TUR yields, on average, a further reduction of recurrence by 1417%, but has limited benefits against disease progression .
BCG vs chemotherapy Compared to several chemotherapeutic agents , BCG is more effective in preventing tumor recurrence and disease progression . In patients with stage Ta or T1 carcinoma, BCG showed a lower recurrence rate and lower disease progression , compared to standard albeit suboptimal MMC treatments . Patients who failed BCG and desired avoiding radical cystectomy have been treated with intravesical IFN- , valrubicin or gemcitabine with some limited success.
Mechanism Of Action Of Intravesical Bcg
To help guide future implications for intravesical treatment in COVID-19 and immunological disorders, it is crucial to review our understanding of the mechanisms of action for BCG intravesical therapy. As previously discussed, there are two branches of intravesical therapy for the treatment of bladder cancer: chemotherapy and immunotherapy. Overall, immunotherapy acts with the patients immune system to upregulate and encourage destruction of cancer cells.
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