Current Perspectives on Immunotherapy in the Peri-Operative Setting of Muscle-Infiltrating Bladder Cancer

Abstract

Patients with muscle-infiltrating bladder cancer (MIBC) present a high risk of postoperative recurrence and death from metastatic urothelial cancer despite surgical resection. Before the use of peri-operative chemotherapy, about half (52%) of patients undergoing radical cystectomy had had a relapse of tumor disease within 5 years of surgery. However, when peri-operative cisplatin-based chemotherapy is added to radical cystectomy for patients with MIBC it provides limited benefit in terms of survival, disease recurrence and development of metastases, at the expense of toxic effects. In fact, a significant proportion of patients still recurs and die to metastatic disease. Given the success of immune-oncological drugs in metastatic urothelial cancer, several trials started to test them in patients with non-metastatic MIBC either in neo-adjuvant and adjuvant setting. The preliminary results of these studies in neo-adjuvant setting are showing great promise, confirming the potential benefits of immunotherapy also in patients with non-metastatic MIBC. The aim of this review is to present an overview of developments happening on the introduction of immunotherapy in peri-operative setting in non-metastatic urothelial cancer. Moreover, an analysis of the critical issues regarding how best customize the delivery of immunotherapy to optimize efficacy and minimize the adverse effects, with particular focus on potential prognostic and predictive molecular biomarkers, is done.

MTHFD2 is a potential oncogene for its strong association with poor prognosis and high level of immune infiltrates in urothelial carcinomas of bladder

“…PD-L1 inhibitors, Atezolizumab and Durvalumab, were both approved by FDA for the treatment of patients with inoperable or metastatic UCB progressing on platinum-based treatment with positive PD-L1 [ 39 ]. A PD1 inhibitor, Pembrolizumab, has been approved in the first-line treatment of UCB patients ineligible for cisplatin with tumor PD-L1 positive [ 40 ]. These immune checkpoint inhibitors were exhibited to have significant efficacy and bring obvious survival benefits to patients with metastatic UCB [ 39 ].…”

An effective N6-methyladenosine-related long non-coding RNA prognostic signature for predicting the prognosis of patients with bladder cancer

“…Recently, many studies have focused on immune checkpoint molecules, such as CTLA-4 and PD-1/PD-L1, as components of new strategies for cancer therapy, and found that these molecules can significantly regulate the immune function of TICs [ 41 , 42 ]. BLCA is immune-responsive, and the efficacy and safety of immunotherapy in peri-operative settings in non-metastatic BLCA are being assessed in several trials [ 43 ]. Furthermore, m6A RNA modification is gaining increasing attention as a potential determinant of therapeutic resistance, including immunotherapy resistance within various cancers, and several lncRNAs have also been shown to affect the outcomes of immunotherapy [ 32 , 44 , 45 ].…”

Role of Perioperative Immune Checkpoint Inhibitors in Muscle Invasive Bladder Cancer

“…For example, there is a lack of threshold standardization to determine whether a tumor is 'positive' or 'negative' in terms of biomarker presence. Expression of PD-L1 is the most widely studied in the field, and a correlation between higher PD-L1 expression on tumor cells and response to ICI has been seen in other cancers [29]. In bladder cancer studies, PD-L1 expression has been linked to advanced pathological stages at the time of cystectomy, and to high mortality, which does suggest the biomarker may have a prognostic role.…”