Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

Abstract

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

Can Smoking Cause Differences in Urine Microbiome in Male Patients With Bladder Cancer? A Retrospective Study

“…Moreover, the intestinal microbiota indirectly affects the metabolism of oral and systemic chemotherapy drugs by regulating gene expression and the physiological effects of local mucosal barriers and distant organs (42)(43)(44)(45)(46). Immune checkpoint inhibitors, antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) or its programmed cell death protein ligand 1 (PDL1), have strong anti-tumor ability in experimental animal models and have shown clinical efficacy in cancers including bladder cancer (47)(48)(49)(50)(51). Recent studies have reported that the intestinal flora is also involved in the treatment of cancer with anti-CTLA4 and anti-PDL1 (50,52).…”

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

“…Standard intravesical therapies include chemotherapy agents such as mitomycin C, gemcitabine, epirubicin, docetaxel, doxorubicin, valrubicin, cisplatin, and thiotepa, among others. Immunotherapy is also considered, where Bacillus Calmette-Guerin (BCG) is preferred, but several other treatments are used, such as interferon and immune checkpoint inhibitors [82,94].On the other hand, MIBC treatment may consist of neoadjuvant chemotherapy with cisplatin and cystectomy; combinations of cisplatin, methotrexate, and vinblastine chemotherapy with cystectomy and/or radiotherapy have been investigated and proposed with improvement outcomes, although eligibility for cisplatin-based chemotherapy should take into account several criteria to minimize the toxicity of the treatment. Radical cystectomy alone is the most used MIBC treatment, and neoadjuvant therapy before cystectomy is not considered to be standard for the trimodal treatment of MIBC [95][96][97][98].…”

“…BCG-based immunotherapy remains ineffective in some NMIBC patients, although efforts have been made to characterize the response, giving the opportunity of an early selection of strategies for the patients who do not benefit from BCG treatment [99]. The expression of several biomarkers related to immune response correlate with resistance to BCG treatment; immune checkpoint inhibitors are complements for the therapy, in particular PD-L1 inhibitors, such as atezolizumab, nivolumab, pembrolizumab, avelumab, and durvalumab [94].…”

The Efficacy of Intra-Arterial Plus Intravesical Chemotherapy Versus Intravesical Chemotherapy Alone After Bladder-Sparing Surgery in High-Risk Bladder Cancer: A Systematic Review and Meta-Analysis of Comparative Study

“…Immune checkpoint inhibitors have increasingly become a therapeutic option for many solid tumors ( 42 , 43 ). In BC, high expression of anti-programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been found to be closely related with advanced and aggressive tumors with lower survival rate ( 44 , 45 ). In this case, PD-1/PD-L1 inhibitors combined with or without BCG are being validated in NMIBC with promising results.…”