The Evolution of Immune Checkpoint Inhibitors in Advanced Urothelial Carcinoma

Abstract

Urothelial carcinoma is an aggressive cancer and development of metastases remains a challenge for clinicians. Immune checkpoint inhibitors (ICIs) are significantly improving the outcomes of patients with metastatic urothelial cancer (mUC). These agents were first used in monotherapy after failure of platinum-based chemotherapy, but different strategies explored the optimal use of ICIs in a first-line metastatic setting. The "maintenance" strategy consists of the introduction of ICIs in patients who experienced benefit from first-line chemotherapy in a metastatic setting. This allows an earlier use of ICIs, without waiting for disease progression. We review the optimal management of mUC in the era of ICIs, based on the key clinical messages arising from the pivotal trials.

Keywords: PD-L1; combined positive score; immune checkpoint inhibitors; maintenance strategy; tumor mutation burden; urothelial carcinoma.

Figure 1

The priming phase consists of the activation of T-cells by antigen-presenting cells (APCs) in lymph nodes. These neoantigens allow the binding of MHCs on APCs to TCRs on T-cells, inducing co-activation signals (B7-CD28) that result in the activation of T-cells. Activated T-cells, in turn, infiltrate tumors and kill tumor cells by enhancing inflammatory reactions. Malignant cells develop different mechanisms to evade immune recognition, including the upregulation of immune checkpoints, such as CTLA-4 and PD-1, on tumor-specific lymphocytes, and PD-L1 on tumor cells themselves. The binding of these immune chekpoints leads to decreased activity of immunological action of T-cells and impairs their capacity to infiltrate tumors and activate inflammatory reactions.

Figure 2

In tumor cells, oncogenic activation of PI3K–Akt–mTOR and MAPK and loss of PTEN induces overexpression of PD-L1 via stimulation of protein synthesis. In T-cells, PD-1 expression inhibits downstream activation of the PI3K–Akt–mTOR and MAPK pathways, inhibits cell cycle progression and negatively regulates T-cell receptor activity.

Figure 3

Current management of metastatic UC in a first-line setting.

Figure 4

Bladder cancer was characterized by a highly immunosuppressive environment. Tumor cells secrete various immunosuppressive and anti-apoptotic factors (vascular endothelial growth factor (VEGF), TGF-β, IL-10 and IL-6, prostaglandine E2 (PGE2)) that create a tolerogenic microenvironment with accumulation of ICs harboring immunosuppressive phenotypes.