Immunotherapy: a new treatment paradigm in bladder cancer

Abstract

Purpose of reviewT-cell checkpoint blockade has become a dynamic immunotherapy for bladder cancer. In 2016, atezolizumab, an immune checkpoint inhibitor, became the first new drug approved in metastatic urothelial carcinoma (mUC) in over 30 years. In 2017, nivolumab was also approved for the same indication. This overview of checkpoint inhibitors in clinical trials focuses on novel immunotherapy combinations, predictive biomarkers including mutational load and neoantigen identification, and an evaluation of the future of bladder cancer immunotherapy.Recent findingsProgramed cell death protein 1/programed death-ligand 1 (PD-1/PD-L1) checkpoint inhibitors have achieved durable clinical responses in a subset of previously treated and treatment-naïve patients with mUC. The combination of PD-1 and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has successfully improved response rates in multiple malignancies, and combination studies are underway in many tumor types, including bladder cancer, combining T-cell checkpoint blockade with other checkpoint agents and immunomodulatory therapies. Strong tumor responses to checkpoint blockade have been reported to be positively associated with expression of PD-L1 on tumor and tumor-infiltrating immune cells and with increased mutation-associated neoantigen load, which may lead to the development of predictive biomarkers.SummaryRecent clinical evidence suggests that mUC is susceptible to T-cell checkpoint blockade. A global effort is underway to achieve higher response rates and more durable remissions, accelerate the development of immunotherapies, employ combination therapies, and test novel immune targets.

Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation

“…45 The possibility of combination therapy upregulating mechanisms of resistance pathways will need to be further explored in our model. Recent US Food and Drug Administration approval of atezolizumab (anti-PD-L1mAb) and nivolumab (anti-PD -1mAb) for treatment of metastatic urothelial carcinoma 46 has brought into question the role of immune therapy earlier in the treatment of UC. Our analysis of patients who have undergone Ad-IFNα/Syn3 (Instiladrin) therapy showed upregulation of cytokines key for immune infiltration, T cell markers, and PD-L1 (and CTLA-4) immune evasion markers, suggesting that these patients may be prime candidates for PD-1 blockade in addition to their gene therapy.…”

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…Other immune-checkpoint players such as cytotoxic T lymphocyte-associated antigen (CTLA-4), which is expressed in T lymphocytes surface and binds B7 on antigen-presenting cells (APCs)-thus impeding the co-stimulatory signal necessary for T-cell activation-also constitutes a target for immune-checkpoint inhibitors, like Ipilimumab. In fact, combinations of both types of inhibitors (anti-PD-1/PD-L1 combined with anti-CTLA-4 agents) are currently undergoing clinical trials for BlCa patients [31,32], following the success observed in melanoma patients [33].…”

Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients

“…Treatment-related side effects of fatigue, and the impact on daily activities, are also reported as relevant to these patients [5], as well as issues with self-esteem, embarrassment, and difficulty engaging in sexual relationships [4, 7, 8]. Emerging novel treatments [9] have accelerated interest in developing and validating patient-reported outcome (PRO) collection instruments to gain a full understanding of UC and disease impact, information important for patients and clinicians. In addition, PRO data can inform the benefit/risk assessment for regulators and payers [10].…”