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Immunotherapy and urinary bladder cancer

Timothy Allen

Global Allied Pharmaceuticals, Center for Excellence in Research and Development, 160 Vista Oak Dr. Longwood, FL 32779, USA

E-mail : aa

Nepton Sheikh-Khoni

Global Allied Pharmaceuticals, Center for Excellence in Research and Development, 160 Vista Oak Dr. Longwood, FL 32779, USA

Naveed Basha Court

Hyderabad, India

DOI: 10.15761/CRR.1000110

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Abstract

Bladder cancer is a type of cancer, which arises from the epithelial lining (urothelium) of the urinary bladder due to the uncontrolled growth of abnormal cells in the bladder. Transitional cell carcinoma (TCC) is the most common type of cancer, involving urinary bladder. It is one of the leading causes of death, worldwide. As per statistical analysis, it is the 7th leading cancer in men worldwide and 17th leading cancer in women worldwide. The bladder cancer represents 4.5% of all the new cancer cases in U.S. The bladder cancer is mainly of three types: Transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma. The molecular instabilities and abnormal metabolic pathways play a key role in the development of urinary bladder cancer and its progression. Intravesical immunotherapy has been approved by FDA for the treatment of urinary bladder cancer and some other drugs, vaccines, and therapies are in clinical trials for FDA approval. Everolimus, sorfenib, and suitinib are highly potential agents for the treatment of urinary bladder cancer and are under clinical trials. Researchers are still challenged in exploring innate and adaptive immune systems.

Key words

epithelial lining (urothelium), transitional cell carcinoma (TCC), squamous cell carcinoma, and adenocarcinoma, altered metabolism/detoxification of carcinogens, inherent or acquired genetic abnormalities, tumor suppressor genes (TSG), intravesical immunotherapy, bacillus calmette-guerin (BCG), transurethral resection (TUR)

Abbreviations

ASR: Age standardized incidence rate; BER: Base excision repair; BCG: Bacillus calmette-guerin; DSB: Double-strand break; MABs: Monoclonal antibodies; NER: Nucleotide excision repair; TCC: Transitional cell carcinoma; TUR: Transurethral resection

Introduction and epidemiology

Bladder cancer is a type of cancer, which arises from the epithelial lining (urothelium) of the urinary bladder. Transitional cell carcinoma (TCC) is the most common type of cancer, involving urinary bladder. However, squamous cell carcinoma, neuroendocrine tumors as well as sarcoma and lymphoma may be present in the bladder, less frequently [1].

Urinary bladder cancer is one of the leading causes of death, worldwide. As per American Cancer Society in United States in 2014, around 74,690 new cases were diagnosed (about 56,390 in men and 18,300 in women), and in the same year around 15,580 cases of death were reported due to bladder cancer (about 11,170 in men and 4,410 in women) [2]. As per statistical analysis, it is the 7th leading cancer in men worldwide and 17th leading cancer in women worldwide [3]. Egypt, Spain, Italy, Zambia and Netherland have high incidence rates as compared to rest of the world. Cancer is caused primarily due to uncontrolled growth of abnormal cells in the urinary bladder [4]. The bladder cancer represents 4.5% of all the new cancer cases in U.S. [5].

The age standardized incidence is 10.1 per 100,000 for men and 2.5 per 100,000 for women worldwide. The worldwide age standardized incidence rate (ASR) is 10.1 per 100,000 for males and 2.5 per 100,000 for females [6]. It includes different type of the histopathologic and genetic characteristics. Generally, bladder cancer occurs in the old age people, and around 9 out of 10 people, over the age of 55, are diagnosed with this cancer. The chances of bladder cancer throughout the life are about 1 in 26 in men and 1 in 90 in women [2].

Etiology and predisposing factors

Bladder cancer is a type of cancer, which arises from the epithelial lining (urothelium) of the urinary bladder due to the uncontrolled growth of abnormal cells in the bladder. The bladder cancer is mainly of three types: Transitional cell carcinoma, squamous cell carcinoma, and adenocarcinoma [6]. The most common symptom of bladder cancer is painless hematuria, however, in advanced cases, pain in lower abdomen resulting from pelvic wall extension, and bone pain due to metastatic involvement might be clinically present [7]. Etiological factors, which contribute to the progression of disease include smoking, age, gender, chronic bladder irritation and infections, personal history of bladder or other epithelial cancer, congenital abnormalities or defects of bladder wall, genetics and family history, chemotherapy and radiation therapy, arsenic in drinking water, and low fluid consumption [2].

Pathophysiology and molecular basis

The molecular instabilities and abnormal metabolic pathways play a key role in the development of urinary bladder cancer and its progression. They include1) altered metabolism/detoxification of carcinogens, and 2) inherent or acquired genetic abnormalities, which may encourage tumor growth, impair DNA repair, or inhibit tumor cell proliferation (tumor suppressor genes) [8,9]. The pathways involved in the altered chemical metabolism of exogenous carcinogens, include N-acetyltransferase genetic and metabolic derangements, glutathione-s-transferase abnormalities, and aberrant cytochrome P450 metabolism (associated genetic defects) pathways [10-13]. The DNA abnormalities may be acquired or inherent, secondary to carcinogenic exposure. Genetic instability may result in the abnormal activity of oncogenes, such as RAS and MYC families, resulting in resistance to apoptosis, cellular proliferation, and aberrant protein expression, such as GDP/GTP binding proteins [13,14]. The tumor suppressor gene abnormalities related with urinary bladder cancer have also been well studied and comprise Rb (retinoblastoma), p16, p21, and p53 tumor suppressor genes, which may be inactivated or mutated. Some defects may thereby, predispose to cell cycle dysregulation and the progression and development of tumor cells [15-18]. Alterations in DNA repair, such as double-strand break (DSB) repair genes, Base excision repair (BER) genes, and Nucleotide excision repair (NER) genes have similarly been related with polymorphisms, which may result in urinary bladder cancer [13,19,20]. Other potential acquired and inherent pathways have also been recognized and may also be involved, including telomere dysfunction, cellular inflammation, and apoptosis [21,22].

Immunotherapy

Monoclonal antibodies (MABs)

Non-FDA approved drugs: (Table 1)

Table 1. Non-FDA approved monoclonal antibodies [23-25]

MABs

Clinical trial identifier number

Phase

Study design

Target

Panitumumab

NCT01916109

Phase II

Safety/Efficacy Study, Open Label

EGF stimulation

GSK2849330

NCT01966445

Phase I

Non-Randomized, Safety Study, Open Label

HER3

SAR408701

NCT02187848

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

CEACAM5

Checkpoint inhibitors

Non-FDA approved drugs: (Table 2)

Table 2. Non-FDA approved checkpoint inhibitors [26-28]

Checkpoint Inhibitors

Clinical trial identifier number

Phase

Study design

Target

MPDL3280A

NCT02302807

Phase III

Randomized, Open label, Safety/Efficacy study

PDL1

Pembrolizumab

NCT02256436

Phase III

Randomized, Open label, Efficacy study

PDL1

Ipilimumab

NCT01928394

Phase II

Randomized, Efficacy Study, Open Label

CTLA-4

Nivolumab

NCT01928394

Phase I

Randomized, Efficacy Study, Open Label

CTLA-4

Vaccine based immunotherapy

Non-FDA approved vaccines: (Table 3)

Table 3. Non-FDA approved vaccines [29]  

Vaccine

Clinical trial identifier number

Phase

Study design

Target

DEC-205-NY-ESO-1

NCT01522820

Phase I

Non-Randomized, Safety Study, Open Label

Bladder cancer cells

Kinase inhibitors

Non-FDA approved drugs: (Table 4)

Table 4. Non-FDA approved kinase inhibitors [30-40]

Kinase inhibitors

Clinical trial identifier number

Phase

Study design

Target

Sorafenib

NCT00772694

Phase II

Efficacy Study, Open Label

RAF/VEGF

Sunitinib

NCT00526656

Phase II

Single Group Assignment, Open Label

VEGF

Pazopanib

NCT01108055

Phase II

Non-Randomized, Safety/Efficacy Study, Open Label

VEGFR, PDGFR

Cabozantinib

NCT01688999

Phase II

Open Label, Efficacy Study

RTKs

Neratinib

NCT01953926

Phase II

Non-Randomized, Safety/Efficacy Study, Open Label

EGFR

Afatinib

NCT02122172

Phase II

Open Label, Efficacy Study

EGFR

Erlotinib

NCT02169284

Phase II

Randomized, Dpuble Blind, Efficacy Study

EGFR

BBI503

NCT02232646

Phase II

Safety/Efficacy Study, Open Label

CSC

Vemurafenib

NCT02304809

Phase II

Safety/Efficacy Study, Open Label

BRAF

Palbociclib

NCT02334527

Phase II

Open Label, Efficacy Study

CDK4 and 6

Alisertib

NCT02109328

Phase I/II

Randomized, Single Blind, Efficacy Study

Aurora A kinase

Growth factor receptor inhibitors

Non-FDA approved drugs: (Table 5)

Table 5. Non-FDA approved growth factor receptor inhibitors [41]

Growth factor inhibitors

Clinical trial identifier number

Phase

Study design

Target

JNJ-42756493

NCT02365597

Phase II

Randomized, Safety/Efficacy Study, Open Label

FGFR

mTOR inhibitors

Non-FDA approved drugs: (Table 6)

Table 6. Non-FDA approved tyrosine kinase inhibitor [42,43]

mTOR Inhibitor

Clinical trial identifier number

Phase

Study design

Target

Everolimus

NCT01466231

Phase II

Efficacy Study, Open Label

mTOR

Sirolimus

NCT01938573

Phase I/II

Safety/Efficacy Study, Open Label

mTOR

Intravesical immunotherapy

Bacillus Calmette-Guerin therapy [44]

Bacillus Calmette-Guerin (BCG) is the most efficient intravesical immunotherapy, which is used for the treatment of early stage bladder cancer. BCG is a bacterium, which is associated with the germ and causes tuberculosis, but it does not generally cause serious type of disease [2].

Indications and usage

BCG is indicated for the prophylaxis and treatment of carcinoma in situ of urinary bladder cancer, and used for the prophylaxis of primary stage Ta or T1 papillary tumors, following transurethral resection (TUR). BCG is not suggested for the stage TaG1 papillary tumors, if they are concluded to be at high risk of tumor repetition.

Contraindication

  • BCG should not be used in immunosuppressed patients or patients with acquired or congenital immune deficiencies, whether due to immunosuppressive therapy, cancer therapy or concurrent disease such as AIDS.
  • Treatment should be delayed until declaration of a concurrent gross hematuria, urinary tract infection, or febrile illness.
  • BCG should not be administered to patients with active tuberculosis.

Warning

  • BCG LIVE is not a vaccine, which is used for the prevention of cancer. BCG vaccine, U.S.P., not BCG LIVE, must be used for the prevention of tuberculosis.
  • Instillation of BCG with actively bleeding mucosa may promote systemic BCG infection. Therefore, the treatment must be delayed for at least one week following TUR, traumatic catheterization, biopsy, or gross hematuria.
  • The use of BCG may cause the tuberculin sensitivity. Since, this is a valuable aid in the diagnosis of tuberculosis, it is advisable to determine the tuberculin reactivity by PPD skin testing before the treatment.
  • Small bladder capacity has been associated with increased risk of severe local reactions and should be considered in deciding to use BCG therapy.

Adverse effects

Hematuria, flu-like syndrome, urinary frequency, dysuria, malaise/fatigue, fever, nausea/vomiting, rigors, cramps/pain, nocturia, urgency, and cystitis are the most common adverse effects of BCG.

Mechanism of Action

The mechanism of action of bacillus Calmette-Guérin (BCG) therapy is partly understood. Some early studies proposed that an immune response against the BCG surface antigens cross-reacted with bladder cancer antigens, and this was projected as the mechanism of action for the different therapeutic effect of BCG; though, multiple following studies disprove this claim.

The live organism enters macrophages in the urinary bladder, where they induce the same type of immunologic and histologic reaction, as established in the patients with tuberculosis. BCG vaccine also has been shown to have a predilection for entering bladder cancer cells, where the proteins are broken down and other fragments are combined with histocompatibility antigens and monitored on the cell surface. This induces cytokines and direct cell-to-cell cytotoxity response, which targets these cells for destruction.

Heat shock protein inhibitors

Non-FDA approved drugs: (Table 7)

Table 7. Non-FDA approved heat shock protein inhibitors [45]

HSP inhibitors

Clinical trial identifier number

Phase

Study design

Target

SNX-5422

NCT01848756

Phase I/II

Open Label, Safety/Efficacy Study

Hsp90

Cytokine therapy

Non-FDA approved drugs: (Table 8)

Table 8. Non-FDA approved cytokine therapy [46]

Cytokine

Clinical trial identifier number

Phase

Study design

Target

ALT-801

NCT01326871

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

Bladder cancer cells

Cancer cell stemness inhibitor

Non-FDA approved drugs: ()

Proteasome inhibitor:

Ixazomib citrate

This drug along with Gemcitabine Hydrochloride and Doxorubicin Hydrochloride in Treating Patients with Urothelial Cancer That is Metastatic or Cannot Be Removed by Surgery (Table 10).

Table 9. Non-FDA approved cancer cell stemness inhibitor [47]

CCS Inhibitors

Clinical trial identifier number

Phase

Study design

Target

BBI608

NCT01325441

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

CSC

Table 10. Proteosome inhibitor

Drug

Clinical trial identifier number

Phase

Study design

Target

Ixazomib Citrate

NCT02420847

Phase I/II

A Phase I Two-Dimensional Dose-Finding Study Followed by a Phase II Extension to Assess the Efficacy

PI3K/AKT Pathway

Oncolytic virus treatment

The oncolytic virus therapy that is under clinical trial phase I-III is given in Table-11 below. The purpose of the study was to evaluate the safety and efficacy of CG0070, an oncolytic virus expression GMCSF in high grade non-muscle invasive bladder cancer patients who failed BCG therapy and refused cystectomy (Table 11).

Table 11. Oncolytic virus therapy

Oncolytic virus

Clinical trial identifier number

Phase

Study design

Target

CG0070

NCT02365818

Phase III

Open label, single arm, multicenter study of the safety and efficacy

GMCSF

Conclusion

There has been a promising development in the immunotherapy in the past few years. Intravesical immunotherapy has been approved by FDA for the treatment of urinary bladder cancer and some other drugs, vaccines, and therapies are in clinical trials for FDA approval. Everolimus, sorfenib, and suitinib are highly potential agents for the treatment of urinary bladder cancer and are under clinical trials. Our success in treating urinary bladder cancer is increasing and advancing with the knowledge of the function of the immune system. Researchers are still challenged in exploring innate and adaptive immune systems.

 

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Editorial Information

Editor-in-Chief

Dung-Fang Lee
The University of Texas

Article Type

Short Communication

Publication history

Received date: January 11, 2017
Accepted date: February 04, 2017
Published date: February 07, 2017

Copyright

Copyright: ©2017 Allen T. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Allen T (2017) Immunotherapy and urinary bladder cancer. Cancer Rep Rev 1: DOI: 10.15761/CRR.1000110

Corresponding author

Timothy Allen

Global Allied Pharmaceuticals, Center for Excellence in Research and Development, 160 Vista Oak Dr. Longwood, FL 32779, USA

Table 1. Non-FDA approved monoclonal antibodies [23-25]

MABs

Clinical trial identifier number

Phase

Study design

Target

Panitumumab

NCT01916109

Phase II

Safety/Efficacy Study, Open Label

EGF stimulation

GSK2849330

NCT01966445

Phase I

Non-Randomized, Safety Study, Open Label

HER3

SAR408701

NCT02187848

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

CEACAM5

Table 2. Non-FDA approved checkpoint inhibitors [26-28]

Checkpoint Inhibitors

Clinical trial identifier number

Phase

Study design

Target

MPDL3280A

NCT02302807

Phase III

Randomized, Open label, Safety/Efficacy study

PDL1

Pembrolizumab

NCT02256436

Phase III

Randomized, Open label, Efficacy study

PDL1

Ipilimumab

NCT01928394

Phase II

Randomized, Efficacy Study, Open Label

CTLA-4

Nivolumab

NCT01928394

Phase I

Randomized, Efficacy Study, Open Label

CTLA-4

Table 3. Non-FDA approved vaccines [29]  

Vaccine

Clinical trial identifier number

Phase

Study design

Target

DEC-205-NY-ESO-1

NCT01522820

Phase I

Non-Randomized, Safety Study, Open Label

Bladder cancer cells

Table 4. Non-FDA approved kinase inhibitors [30-40]

Kinase inhibitors

Clinical trial identifier number

Phase

Study design

Target

Sorafenib

NCT00772694

Phase II

Efficacy Study, Open Label

RAF/VEGF

Sunitinib

NCT00526656

Phase II

Single Group Assignment, Open Label

VEGF

Pazopanib

NCT01108055

Phase II

Non-Randomized, Safety/Efficacy Study, Open Label

VEGFR, PDGFR

Cabozantinib

NCT01688999

Phase II

Open Label, Efficacy Study

RTKs

Neratinib

NCT01953926

Phase II

Non-Randomized, Safety/Efficacy Study, Open Label

EGFR

Afatinib

NCT02122172

Phase II

Open Label, Efficacy Study

EGFR

Erlotinib

NCT02169284

Phase II

Randomized, Dpuble Blind, Efficacy Study

EGFR

BBI503

NCT02232646

Phase II

Safety/Efficacy Study, Open Label

CSC

Vemurafenib

NCT02304809

Phase II

Safety/Efficacy Study, Open Label

BRAF

Palbociclib

NCT02334527

Phase II

Open Label, Efficacy Study

CDK4 and 6

Alisertib

NCT02109328

Phase I/II

Randomized, Single Blind, Efficacy Study

Aurora A kinase

Table 5. Non-FDA approved growth factor receptor inhibitors [41]

Growth factor inhibitors

Clinical trial identifier number

Phase

Study design

Target

JNJ-42756493

NCT02365597

Phase II

Randomized, Safety/Efficacy Study, Open Label

FGFR

Table 6. Non-FDA approved tyrosine kinase inhibitor [42,43]

mTOR Inhibitor

Clinical trial identifier number

Phase

Study design

Target

Everolimus

NCT01466231

Phase II

Efficacy Study, Open Label

mTOR

Sirolimus

NCT01938573

Phase I/II

Safety/Efficacy Study, Open Label

mTOR

Table 7. Non-FDA approved heat shock protein inhibitors [45]

HSP inhibitors

Clinical trial identifier number

Phase

Study design

Target

SNX-5422

NCT01848756

Phase I/II

Open Label, Safety/Efficacy Study

Hsp90

Table 8. Non-FDA approved cytokine therapy [46]

Cytokine

Clinical trial identifier number

Phase

Study design

Target

ALT-801

NCT01326871

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

Bladder cancer cells

Table 9. Non-FDA approved cancer cell stemness inhibitor [47]

CCS Inhibitors

Clinical trial identifier number

Phase

Study design

Target

BBI608

NCT01325441

Phase I/II

Non-Randomized, Open Label, Safety/Efficacy Study

CSC

Table 10. Proteosome inhibitor

Drug

Clinical trial identifier number

Phase

Study design

Target

Ixazomib Citrate

NCT02420847

Phase I/II

A Phase I Two-Dimensional Dose-Finding Study Followed by a Phase II Extension to Assess the Efficacy

PI3K/AKT Pathway

Table 11. Oncolytic virus therapy

Oncolytic virus

Clinical trial identifier number

Phase

Study design

Target

CG0070

NCT02365818

Phase III

Open label, single arm, multicenter study of the safety and efficacy

GMCSF