Seminar article
Emerging role of immunotherapy in urothelial carcinoma—Immunobiology/biomarkers

https://doi.org/10.1016/j.urolonc.2016.10.006Get rights and content

Abstract

Urothelial bladder cancer is one of the first cancers recognized to be immunogenic since 40 years ago when the use of bacillus Calmette–Guerin was shown to prevent recurrence. Since that time, our knowledge of immune biology of cancer has expanded tremendously, and patients with bladder cancer finally have new active immunotherapeutic drugs on the horizon. Anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) therapy has shown impressively durable responses in urothelial bladder cancer (UBC), but the reported response rates warrant improvement. To outline potential strategies to overcome tumor immune resistance, herein, we summarize current models of tumor immunology with a specific focus on bladder cancer. Recognition of tumor-specific antigens through cross-presentation, T-cell priming and activation, and trafficking of immune cells to the tumor microenvironment are some of the critical steps we now understand to be necessary for an effective antitumor immune response. Many of the involved steps are important targets for therapeutic interventions. As new immunotherapies are developed, predictive biomarkers would also be important to select patients most likely to respond and to better understand tumor biology. Several potential biomarkers are reviewed including PD-L1 expression, identification of T-cell-inflamed/non–T-cell-inflamed tumors based on immune gene expression, intrinsic molecular subtyping based on luminal/basal or the cancer genome atlas (TCGA) groups, T-cell receptor sequencing, and somatic mutational density. Even within the past few years, our current knowledge of immune biology has exploded, and we are highly optimistic about the future of UBC therapy that will be available to patients.

Introduction

Decades of efforts aimed at elucidating the biology of cancer immunity have now finally begun to bear fruit for patients in the clinic. Immunotherapy for bladder cancer was reported as early as 1976, when Alvaro Morales reported the successful intravesicular treatment of 9 patients with tuberculosis vaccine bacillus Calmette–Guerin (BCG) [1]. Expanded studies confirmed the efficacy of BCG leading to United States Food and Drug Administration approval in 1990 as the second cancer immunotherapy, behind only interferon-alpha. Since that time, only a single additional drug has secured regulatory approval for the treatment of bladder cancer, valrubicin, in 1998 [2]. Given the paucity of new treatments over the past 20 years (Fig. 1) for a disease responsible for over 165,000 deaths per year worldwide [3], identification of novel therapeutic targets has been a key priority in the field.

Our understanding of bladder cancer immunobiology has grown tremendously since the approval of BCG. Several potential mechanisms underlying the anticancer effects of BCG have been identified including activation of the innate immune response though toll-like receptors, recruitment of immune cells through cytokine production, and direct cytotoxicity [4]. With the recent successes of immune checkpoint inhibitors in metastatic UBC [5], [6], [7], [8], researchers have again brought bladder cancer to the forefront of immunotherapy. There now remains a continued urgency to build upon the early success with immune checkpoint blockade and identify biomarkers to guide patient selection and identify rational combination approaches. This article examines our current knowledge of the immunobiology of UBC and discusses potential future approaches to improve therapeutic responses to immunotherapy.

Section snippets

Components of effective antitumor immunity

When intact and unperturbed, the human immune system can recognize and eradicate abnormal malignant cells. This process is clearly disrupted in patients who develop cancers or have progression during therapy. To develop novel strategies for immunotherapy in UBC, the events required for an effective antitumor immune response must be appreciated. First, the process of oncogenesis generally leads to genetic instability and the occurrence of nonsynonymous somatic mutations. Such mutations encode

Therapeutic targeting of dysfunctional antitumor immunity

Strategies to reestablish the elements of cancer immunity that are circumvented by tumors have now resulted in an eruption of novel cancer immunotherapeutics. In tumors believed to lack a tumor antigen–specific T-cell response, the use of therapeutic vaccines to stimulate an adaptive immune response is being investigated [30]. Vaccines use one or more tumor-associated or tumor-specific antigens. The latter is preferred since tumor-associated antigens may be variably expressed in normal tissues,

Development of predictive biomarkers

As new immunotherapeutic drugs are being developed at a rapid pace, there is an ongoing need to concurrently identify predictive biomarkers to personalize our therapeutic algorithms. Much excitement has been generated in UBC regarding anti-PD-1/PD-L1 therapy, but cancers in most patients still fail to respond. Ideally, clinicians could identify patients highly unlikely to respond and direct them to clinical trials investigating novel approaches. Considerable work has been aimed at this goal in

Conclusion and future directions in bladder cancer immunotherapy

Our growing understanding of immune biology coupled with recent successes in immune checkpoint blockade in UBC now has the potential to truly impact clinical therapeutics for UBC. However, it is humbling to note that patients with advanced disease benefiting from immune checkpoint blockade remain in the minority, only modestly above the historical 10% response rate with chemotherapies. It is therefore incumbent upon us to continue to improve our immunotherapeutic strategies rationally from

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    Supported by National Institutes of Health, United States, Grant nos. T32 CA009566 and T32 GM007019 (R.F.S.).

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