Urologic Oncology: Seminars and Original Investigations
Seminar articleEmerging role of immunotherapy in urothelial carcinoma—Immunobiology/biomarkers☆
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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PD-1/PD-L1 Combinations in Advanced Urothelial Cancer: Rationale and Current Clinical Trials
2019, Clinical Genitourinary CancerCitation Excerpt :TIM-3 expression in UC/BC TMEs worsens clinical outcomes, and high co-expression of TIM-3/PD-1 was prognostically poorer than that of either checkpoint alone.40 Alternate checkpoints, as with PD-1, respond adaptively to attack, as TIM-3 and LAG-3 presentation correlated strongly with CD8A gene expression (a marker for CD8+ T-cells).41 Tumors in mice progressing after initial response to anti-PD-1 therapy (PD resistance) show TIL upregulation of TIM-3 and LAG-3, a therapeutically relevant observation as TIM-3 blockade in the PD resistance stage improves survival.42
Evaluation of PD-L1 biomarker for immune checkpoint inhibitor (PD-1/PD-L1 inhibitors) treatments for urothelial carcinoma patients: A meta-analysis
2019, International ImmunopharmacologyCitation Excerpt :To date, we have five kinds of ICIs for urothelial carcinoma patients, including atezolizumab (anti-PD-L1), nivolumab (anti-PD-1), durvalumab (anti-PD-L1), avelumab (anti-PD-L1), and pembrolizumab (anti-PD-1). Since it is still under debate whether PD-L1 can be selected [27,28], this work represent an attempt to compare PD-L1 biomarkers across five different drugs to identify the feasibility of using PD-L1 in difference ICI treatments, which may help clinicians in their daily practice. With a focus on urothelial carcinoma patients, our results supported that PD-L1 can predict the objective response rate for ICI treatments.
Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial
2018, The Lancet OncologyCitation Excerpt :Additional investigations of biomarkers for urothelial carcinoma and other avelumab-treated patient populations, including tumour mutational burden, gene-expression signatures, and tumour-infiltrating lymphocytes in the tumour microenvironment, are ongoing. Efforts to cross-validate and standardise these diagnostic assays in urothelial carcinoma and other cancers are underway.27,37 The safety profile of avelumab was consistent with reports of avelumab in other tumour types28,31,32,38 and was generally similar to other anti-PD-L1 and anti-PD-1 antibodies in urothelial carcinoma.16–18,20–23
Mechanistic and pharmacologic insights on immune checkpoint inhibitors
2017, Pharmacological ResearchCitation Excerpt :The fourth approved immune checkpoint inhibitor was atezolizumab, which came on the market first for the treatment of urothelial bladder cancer. This was the first approved drug for advanced bladder cancer in over 20 years [38]. It is a human IgG1 antibody targeting PD-L1, in contrast to PD-1.
Immunotherapy in uropathology
2017, Annales de Pathologie
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Supported by National Institutes of Health, United States, Grant nos. T32 CA009566 and T32 GM007019 (R.F.S.).