Inhibiting Immune Checkpoints for the Treatment of Bladder Cancer

Abstract

Background:Increasing evidence supporting the role of immune checkpoint blockade in cancer management has been bolstered by recent reports demonstrating significant and durable clinical responses across multiple tumour types, including metastatic urothelial carcinoma (mUC). The majority of these results are achieved via blockade of the programmed death (PD) axis, which like CTLA-4 blockade permits T-cell activation and immune-mediated anti-tumour activity- essentially harnessing the patient’s own immune system to mount an anti-neoplastic response. However, while clinical responses can be striking, our understanding of the biology of immune checkpoint blockade is only beginning to shed light on how to maximize and even improve patient outcomes with immune checkpoint blockade, especially in UC.Methods:We performed a literature review for immune checkpoint blockade with a focus on rationale for checkpoint therapy and outcomes in UC. We also highlight the advances made in other tumour types, with a focus on the recent 2015 meeting of the American Society for Clinical Oncology.Results:In heavily pre-treated UC, trials are suggesting objective response rates above 30% . These impressive results are seen across multiple different tumour types, especially those with high burden of DNA level mutations. Identification of prognostic biomarkers is currently under investigation, in order to improve patient selection. Interestingly, response to PD-1 directed therapy is seen even in patients with no evidence of PD-1 positivity on immunohistochemistry. This has led to the development of enhanced biomarkers including assessing DNA mutation rates and immune gene signatures, to improve patient selection.Conclusions:Immune checkpoint blockade is an exciting cancer treatment modality which is demonstrating impressive clinical results across multiple tumour types. For UC, anti-PD directed therapy represents a much needed treatment in the metastatic, post chemotherapy context. Potential for these agents to have clinical utility in non-metastatic UC is still to be assessed.

A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now

“…One of the most promising has been the use of monoclonal antibodies to block the negative co-signaling molecules that prevent an effective immune response. The result of these ''checkpoint" inhibitors is the reinvigoration of T-cell-mediated antitumor activity [26].…”

Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more

“…For instance, a promising avenue of clinical research in bladder cancer is the use of immune checkpoint inhibitors that target molecules involved in the balance and regulation of immune response, hence inducing proper T-cell anti-cancer response. [30] In conclusion, the analysis of mRNA expression of PBMCs by real-time PCR was a relatively simple, accurate technique for assessing the expression profile of several key immunomodulators in patients with NMIBC, as compared with classical histopathological evaluations and even with urine detection because not all patients have urine detectable levels.…”

Aktuelle Systemtherapie des Urothelkarzinoms

“…Ein neuer vielversprechender Ansatz, der auf eine Aktivierung des patienteneigenen Immunsystems zur Bekämpfung des Tumors zielt, sind die sogenannten Immuncheckpoint-Inhibitoren. Grob zusammengefasst sollen durch diese Substanzen Regulationsmechanismen aufgehoben werden, die eine Aktivie- [72,73].…”