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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 32  |  Issue : 1  |  Page : 8-13

Immunotherapy for advanced bladder cancer: a new era


Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine-Menoufiya University, Menoufia, Egypt

Date of Submission07-Nov-2017
Date of Acceptance09-Jan-2018
Date of Web Publication17-Apr-2019

Correspondence Address:
Eman Helmy Desoky
8- El Teraa Street, Sector-2, Birket EL Saba City, Menoufiagovernate, 32717
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_768_17

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  Abstract 


Objectives
The aim of this study was to analyze data and current trends in immune checkpoint targeting therapy for bladder cancer.
Data sources
A systematic literature search was performed for clinical trials in the Medline databases (Google Scholar, ClinicalTrials.gov, Cochrane, http://www.ekb.eg) and all materials available in the Internet from 2014 up to 2017 according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
Study selection
The initial search yielded 35 articles, of which 30 fulfilled the inclusion criteria. The articles studied the role of Immune checkpoint targeting therapy in bladder cancer.
Data extraction
If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was obtained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures.
Data synthesis
Comparisons were made by structured review, with the results tabulated.
Findings
Humanized monoclonal antibodies that block CTLA-4 (ipilimumab, tremelimumab), PD-1 (nivolumab, pembrolizumab), or PD-L1 (atezolizumab, durvalumab, avelumab) have all shown antitumor activity in patients with urothelial carcinoma (UC). Atezolizumab and nivolumab are approved by the Food and Drug Administration for second-line therapy for advanced UC and a number of other checkpoint inhibitors are in clinical trials.
Conclusion
Immunotherapy for UC remains a promising and active area of research; intravesical Bacillus Calmette-Guerin has been used as a form of immunotherapy in nonmuscle invasive disease. Also, numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.

Keywords: cancer immunotherapy, checkpoint, CTLA-4, monoclonal antibodies, PD-1, PD-L1


How to cite this article:
ElRazek EA, Alhassanin S, Al Agizy H, Alhanafy AM, Desoky EH. Immunotherapy for advanced bladder cancer: a new era. Menoufia Med J 2019;32:8-13

How to cite this URL:
ElRazek EA, Alhassanin S, Al Agizy H, Alhanafy AM, Desoky EH. Immunotherapy for advanced bladder cancer: a new era. Menoufia Med J [serial online] 2019 [cited 2019 Jul 20];32:8-13. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/8/256144




  Introduction Top


Bladder cancer poses a major disease burden [1], with around 900 000 new cases affected by the disease worldwide and 250 000 deaths occurring per year because of the cancer [2]. It is the ninth most common cancer, the 11th most commonly diagnosed cancer, and the 14th leading cause of deaths because of cancer worldwide [3]. In Egypt, bladder cancer has long been the most commonly diagnosed cancer because of its association with schistosomiasis. Schistosomiasis-associated bladder cancers are predominantly squamous cell carcinomas, but there has been a marked decrease in the incidence of squamous cell carcinomas of the bladder in recent years, whereas the incidence of transitional cell carcinomas has been increasing, particularly in men, probably because of a reduction in Schistosomal infection and increases in the prevalence of cigarette smoking [4]. Urothelial bladder cancer is associated with a relatively high level of somatic mutations, possibly facilitating the immunological recognition of tumor-related neoanigens. These neoanigens are abnormal antigens produced by mutant proteins [5]. In the 1970s, intravesical Bacillus Calmette-Guerin (BCG) was used as a form of immunotherapy in nonmuscle invasive disease. Subsequent randomized trials confirmed reduced rates of recurrence and progression, with positive effects on mortality. In 1990, the Food and Drug Administration (FDA) approved intravesical BCG as the first cancer immunotherapy, and it has since become the gold standard for treating high-risk NMIUC [6]. Atezolizumab and nivolumab are approved by the FDA for second-line therapy for advanced urothelial carcinoma (UC) and a number of other checkpoint inhibitors are in clinical trials [7]. These immune-checkpoint inhibitors have activity in patients with chemotherapy-refractory metastatic urothelial bladder cancer [5]. A brief review of cancer immunology is presented to understand the mechanism of checkpoint inhibitors: to distinguish self from non self, the immune system relies on T-cell receptors recognizing and binding to antigens presented by a protein complex called the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APC) [8]. However, the MHC presents self-antigens as well as foreign antigens, and T cells need to distinguish those that they should attack. When the CD28 protein on the T cell binds to the B7 protein on the APC, the T cell is stimulated. Once stimulated, T cells upregulate the expression of cell-surface proteins called 'immune checkpoints' that help to control the immune response. When engaged with their ligands, checkpoint proteins modulate T-cell activation, Th1 cytokine production, and cell-mediated cytotoxicity [9]. This physiologic 'braking' of the immune system is important because it prevents unchecked inflammation and autoimmunity. In a cancer patient, however, it can allow tumor cells, which would normally be recognized by T cells, to evade the immune system [10]. A large number of checkpoint proteins have been identified, and to date, drugs that inhibit two of them, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), have shown significant clinical activity. CTLA-4 is considered the lead checkpoint because it stops initial T-cell activation, typically in lymph nodes. Monoclonal antibodies against CTLA-4 block the interaction between CTLA-4 and its B7 ligands, enabling the activation of more T cells [7]. The PD-1 pathway is located in the tumor microenvironment, where it dampens ongoing immune responses after T cells have been activated. Unlike CTLA-4, which is expressed only on T cells, PD-1 is expressed on a broad range of cells, including activated and 'exhausted' (nonfunctional) T cells, tumor-infiltrating T cells, and APCs, such as B cells, dendritic cells, and macrophages [8]. The PD-1 pathway consists of the PD-1 receptor and its two ligands: PD-L1 and PD-L2. Both PD-1 and PD-L1 become highly expressed on UC and many types of tumors, and the PD-1/PD-L1 pathway is probably dominant for allowing tumors to escape from the immune system. The PD-2 ligand is expressed by a more limited cell population and has not been well studied [11]. Binding of PD-1 with PD-L1 inhibits T-cell the proliferation and production of Th1 cytokines, and cytolysis activity, which leads to the 'exhaustion' of T cells. Monoclonal antibodies against PD-1 or PD-L1 allow T cells to remain activated, restore the activity of those that have become nonfunctional, and reduce the immunosuppression produced by T regulatory cells [12]. Humanized monoclonal antibodies that block CTLA-4 (ipilimumab, tremelimumab), PD-1 (nivolumab, pembrolizumab), or PD-L1 (atezolizumab, durvalumab, avelumab) have all shown antitumor activity in patients with UC [13] [Figure 1].
Figure 1: Schematic of an immune response to a tumor cell, showing two immune checkpoint pathways (CTLA-4 and PD-1) and opportunities for blocking them.

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The aim of this work was to analyze data and current trends in immune checkpoint targeting therapy for bladder cancer.


  Materials and Methods Top


Search strategy

We reviewed clinical trials.gov, Google scholar, Cochrane, and ekb.eg to find the recently completed and ongoing clinical trials in MUC. Included in this review are clinical trials that are currently active and trials that were completed in and after 2014. We used Cancer immunotherapy/Monoclonal antibodies/Checkpoint/CTLA-4/PD-1/PD-L1/BCG/urothelial bladder cancer as searching terms.

Study selection

All the studies were assessed independently for inclusion. They were included if they fulfilled the following criteria:

Inclusion criteria of the published studies:

Published in the English language

Published in peer-reviewed journals

Focused on immune checkpoint targeting therapy for bladder cancers

Discussed the recent clinical trials in the role of immunotherapy in bladder cancer.

If a study had several publications on certain aspects, we used the latest publication providing the most relevant data.

Data extraction

If the studies did not fulfill the above criteria, they were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and the UK National Health Service protocol for EBM in addition to the Evidence Pyramid.

US Preventive Services Task Force:

Level I: Evidence obtained from at least one properly designed randomized-controlled trial

Level II-1: Evidence obtained from well-designed controlled trials without randomization

Level II-2: Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be considered as this type of evidence

Level III: Opinions of respected authorities, on the basis of clinical experience, descriptive studies, or reports of expert committees.

Quality assessment

The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis carried out in addition to an explanation of missing data.

Data synthesis

A structured systematic review was performed, with the results tabulated.


  Results Top


In total, 35 potentially relevant publications were identified; five articles were excluded as they did not fulfill our inclusion criteria. A total of 30 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. Of these 30 articles included in this review, six articles focused on Nivolumab, four focused on atezolizumab, and 20 articles focused on all immunotherapeutic agents. The studies of nivolumab were CheckMate 275, CheckMate 032, the study of atezolizumab was Cohort 2 of the phase 2 IMvigor 210 trial, the study of pembrolizumab was the KEYNOTE-012 phase 1b trial, and the study of avelumab was a JAVELIN solid tumor phase 1b trial. The studies are analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protoco l for EB M. The results are tabulated in [Table 1].
Table 1: Summary of clinical trials

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  Discussion Top


Recently improved understanding of molecular targets and immunologic characteristics of urothelial tumor cells has resulted in new novel immunotherapeutic agents in the management of cases of advanced UC [7]. These investigational therapies can generally be classified into several broad categories, including recombinant BCG and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies, and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials [14].

Nivolumab is a monoclonal antibody directed against PD-1, and was the first PD-1 inhibitor approved anywhere in the world for the treatment of multiple tumors such as unresectable and metastatic melanoma, non-small-cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, squamous cell cancer of the head and neck, and recently for the treatment of patients with locally advanced or metastatic UC whose disease has progressed over a period of up to 1 year after first-line platinum-containing chemotherapy [15]. The approval of nivolumab in UC was based on CheckMate 275, a multicenter, single-arm, phase 2 trial of nivolumab (3 mg/kg, intravenously once every 2 weeks) in patients (N = 265) with metastatic or advanced UC who had disease progression or recurrence despite at least one platinum-based chemotherapy regimen [16]. The results were an objective response rate (ORR) of 19.6% for the total population, 16.1% in those with low or no PD-L1 tumor expression (<1%), and 28.4% in those with PD-L1 tumor expression of at least 5% after a median 7-month follow-up. The median progression-free survival (PFS) was 2.0 months and the median overall survival (OS) was 8.7 months. A total of 18% of patients experienced grade 3/4 adverse events (fatigue and diarrhea; 2% each) and 1% of patients experienced a grade 5 event [17]. Recent results from the nonrandomized, phase 1/2 CheckMate 032 study (NCT01928394) of nivolumab (3 mg/kg, intravenously once every 2 weeks) in patients (N = 78) with metastatic urothelial cancer showed an ORR of 24% for those with PD-L1 expression more than 1% on tumor cells versus 26% for those with PD-L1 expression of less than 1%, and OS was 9.7 months for the entire population. About 21.8% of patients experienced grade 3/4 adverse events, with increased lipase (5.1%), increased amylase (3.8%), and fatigue, decreased neutrophils, and dyspnea (2.6% each) being the most common; grade 5 pneumonitis and thrombocytopenia occurred in one (2.6%) patient each [16]. A phase 3 study (CheckMate 274; NCT02632409) of nivolumab versus placebo after surgery in patients with bladder or upper urinary tract cancer is ongoing [18].

Atezolizumab was the first PD-L1 inhibitor found active in bladder cancer [19]. Now it is the only PD-L1 inhibitor specifically approved for patients with locally advanced or metastatic UC who progress on or after platinum-based chemotherapy [18]. This monoclonal antibody was granted accelerated approval by the FDA in May 2016, and is pending approval in Europe. The initial studies of atezolizumab from 2014 were in non-small-cell lung cancer, with approval for this indication granted in October 2016. It is still under investigation for renal cell carcinoma, melanoma, triple-negative breast cancer, and others [20]. The FDA approval of atezolizumab in UC was on the basis of cohort 2 of the phase 2 IMvigor 210 trial (NCT02108652) in patients (N = 310) with inoperable, platinum-treated, locally advanced, or metastatic UC. This analysis showed that atezolizumab (1200 mg, intravenously once every 3 weeks) resulted in an ORR of 16% for all patients and a 28% ORR in those with at least 5% of PD-L1 expressing tumor-infiltrating immune cells after 1.5 years of median follow-up [21].

Pembrolizumab is another emerging PD-1 inhibiting antibody, showing antitumor activity in early-phase clinical trials. The KEYNOTE-012 (NCT01848834) phase 1b study showed that among all patients (N = 28) with advanced urothelial cancer, the ORR was 25% and the 12-month PFS rate was 19% for the overall population with pembrolizumab (10 mg/kg every 2 weeks); for patients with tumors positive for PD-L1 expression, the ORR was 38%. Fatigue was the most common adverse event (18%), followed by peripheral edema (12%) and nausea (9%); 15% developed grade 3–5 adverse events [22].

Ipilimumab, a monoclonal anti-CTLA-4 antibody, blocks the B7: CTLA-4 interaction, thus shifting the T-cell equilibrium toward activation and effector function, with subsequent antitumor effects. Successful trials of ipilimumab in metastatic melanoma led to its FDA approval in 2011 [23]. Ipilimumab was evaluated in a small study of 12 patients with bladder cancer to investigate its biological effects on bladder cancer tissue. In this study, patients scheduled for cystectomy for cT1-T2N0M0 disease were administered two doses of the drug beginning ~ 7 weeks before cystectomy. The majority of adverse events were grade 1 or 2, although two patients had a delay in surgery because of immune-related adverse events [24]. A phase II ongoing clinical trial evaluating ipilimumab in combination with gemcitabine and cisplatin in patients with advanced disease was presented at the ASCO 2016 Genitourinary Cancers Symposium and failed to meet its primary endpoint (NCT01524991) [14]. Combination therapy with PD-1/PD-L1 and CTLA-4 inhibition is being investigated in a number of malignancies, including UC (NCT01928394, NCT02496208) [14].

On 1 May 2017, durvalumab, a monoclonal antibody against PD-L1, was granted accelerated approval by FDA for the treatment of patients with locally advanced or metastatic UC who show disease progression during or following platinum-containing chemotherapy or who show disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy [25]. Approval was based on one single-arm trial of 182 patients with locally advanced or metastatic UC whose disease progressed after previous platinum-containing chemotherapy. Durvalumab, 10 mg/kg intravenously, was administered every 2 weeks. In the 182 patients, the confirmed ORR was 26.3% (95% confidence interval: 17.8–36.4) in 95 patients with a high PD-L1 score and 4.1% (95% confidence interval: 0.9–11.5) in 73 patients with a low or a negative PD-L1 score [25].

The most common adverse events were fatigue, diarrhea, and decreased appetite. Grade 3–4 adverse events were found in 43% of patients. Infection and immune-related adverse events such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes were also observed with durvalumab [25].

The combination of durvalumab plus the CTLA-4 inhibitor, tremelimumab, which is currently being examined (DANUBE; NCT02516241), versus standard of-care chemotherapy in patients with stage IV urothelial bladder cancer, is expected to be completed in 2019. This three-arm trial (N = 1004) compares standard chemotherapy with single agent durvalumab and the combination of durvalumab and tremilimumab, with overall survival as the primary endpoint [18].

Avelumab, an anti-PD-L1 monoclonal antibody, is in the initial stages of development for more than 15 types of cancers, including bladder cancer. Avelumab differs from the other PD-L1 inhibitors in that in addition to inhibiting PD-L1, it possesses antibody-dependent, cell-mediated cytotoxicity, which results in direct lysis of tumor cells [26]. Results from the ongoing JAVELIN Solid Tumor phase 1b trial (NCT01772004) presented at the 2016 European Society for Medical Oncology annual meeting showed that the overall ORR was 16.5%, the median PFS was 6.1 weeks, and the PFS rate at 12 weeks was 35.6% for avelumab (10 mg/kg, intravenously once every 2 weeks) in patients with metastatic UC who progressed after platinum-based chemotherapy or were platinum-ineligible (N = 129). The phase 3 JAVELIN Bladder 100 study (NCT02603432) as first-line treatment in the maintenance setting is currently ongoing. This maintenance design is distinct from other studies in the era of immune-oncology therapy [27].

Findings

Humanized monoclonal antibodies that block CTLA-4 (ipilimumab, tremelimumab), PD-1 (nivolumab, pembrolizumab), or PD-L1 (atezolizumab, durvalumab, avelumab) have all shown antitumor activity in patients with UC. Atezolizumab and nivolumab are approved by the FDA for second-line therapy for advanced UC and a number of other checkpoint inhibitors are in clinical trials.


  Conclusion Top


Immunotherapy for UC remains a promising and active area of research; intravesical BCG has been used as a form of immunotherapy in nonmuscle invasive disease. Also, numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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