Checkpoint Inhibition in Bladder Cancer: Clinical Expectations, Current Evidence, and Proposal of Future Strategies Based on a Tumor-Specific Immunobiological Approach

Abstract

In contrast with other strategies, immunotherapy is the only treatment aimed at empowering the immune system to increase the response against tumor growth. Immunotherapy has a role in the treatment of bladder cancer (BC) due to these tumors’ high tumor mutational burden (TMB) and mostly prominent immune infiltrate. The therapy or combination has to be adjusted to the tumor’s immunobiology. Recently, a new class of immunotherapeutic agents, immune checkpoint inhibitors (ICI), has shown potential in increasing treatment chances for patients with genitourinary cancers, improving their oncological outcomes. The clinical efficacy of ICI has been shown in both the first-line treatment of cisplatin-ineligible patients, with programmed death ligand 1 (PD-L1)-positive tumors (atezolizumab, pembrolizumab), and in second-line settings, for progression after platinum-based chemotherapy (atezolizumab, pembrolizumab, and nivolumab for FDA and EMA; durvalumab and avelumab for FDA alone). Predicting the response to ICI is important since only a subset of patients undergoing ICI therapy develop a concrete and lasting response. Most of the patients require a different therapy or therapy combination to achieve tumor control. The cancer immunity cycle provides a conceptual framework to assist therapy selection. Biomarkers to predict response to ICI must identify where the cancer immunity cycle is disrupted. We reviewed the current knowledge on ICI treatment in BC, going from basic science to current data and available clinical evidence. Secondly, a critical analysis of published data is provided, and an original panel of biomarkers able to predict response to ICI treatment, based on tumor-specific immune profiling, is proposed.

Detailed bladder cancer immunoprofiling reveals new clues for immunotherapeutic strategies

“…10,11 However, many patients are not eligible or sensitive to chemotherapy, and high rates of severe adverse events have been reported, 12 entailing the need for effective alternatives. Mounting evidence suggests that neoadjuvant immunotherapy may benefit patients with localised MIBC, 13,14 but further investigation is required to support this hypothesis.…”

Nonsense-Mediated Decay Targeted RNA (ntRNA): Proposal of a ntRNA–miRNA–lncRNA Triple Regulatory Network Usable as Biomarker of Prognostic Risk in Patients with Kidney Cancer

“…Prior research has recognized the importance of immune infiltration for prognosis [ 61 , 62 ]. Moreover, it has recently been hypothesized that therapy, or combination of therapies, in cancer has to be adjusted to the tumor immunobiology; the potential use of immuno-based biomarkers, such as the ones we discovered, has been recently proposed in other urological tumors, such as bladder cancer [ 63 ]. In our study, eight of the 24 different types of immune cells that were associated with our hub triple regulatory network and overall survival of KIRC patients were explored.…”

Current State of Cell Therapies for Genitourinary Malignancies

“…50,51 Half of patients who undergo radical cystectomy will recur within 2 years, and a portion will develop distal metastases. 52,53 This high rate of disease recurrence and lack of therapeutic durability in multiple stages of treatment highlight a gap in bladder cancer disease management. Alternative therapies need to be considered to preclude the progression of disease and maintain response durability.…”