Immune checkpoint inhibitors in urothelial cancer: recent updates and future outlook

Abstract

Bladder cancer is the sixth most common cancer in the US and most tumors have urothelial (transitional cell) histology. Platinum-based chemotherapy has long been the standard of care in advanced disease, but long-term outcomes have largely remained poor. Since the peak incidence of bladder cancer is in the eighth decade of life and beyond, medical comorbidities may often limit the use of chemotherapy. Immune checkpoint inhibitors with their favorable toxicity profiles and notable antitumor activity have ushered in a new era in the treatment of advanced urothelial cancer (UC) with five agents targeting the PD-1/PD-L1 pathway being recently approved by the US Food and Drug administration. A plethora of clinical trials are ongoing in diverse disease settings, employing agents targeting PD-1/PD-L1 and related immune checkpoint pathways. While reactivating anti-tumor immunity, these agents may lead to a unique constellation of immune-related adverse events, which may warrant discontinuation of therapy and potential use of immunosuppression. Novel combinations with various treatment modalities and optimal sequencing of active therapies are being investigated in prospective clinical trials and retrospective registries. At the era of precision molecular medicine, and since patients do not respond uniformly to these agents, there is a growing need for identification and validation of biomarkers that can accurately predict treatment response and assist in patient selection. This review discusses current updates and future directions of immunotherapy in advanced UC.

Impact of performance status on treatment outcomes: A real‐world study of advanced urothelial cancer treated with immune checkpoint inhibitors

“…Although prognostic nomograms have been developed, composite predictive biomarkers (which can aid in decision making) need to demonstrate clinical utility via interrogation in clinical trials . Numerous putative biomarkers, such as PD‐L1 protein expression, the tumor mutational burden, T‐effector, TGF‐β, ΕΜΤ, and other gene signatures, DNA damage response gene and FGFR3 alterations, molecular subtypes, and T‐cell clonality/diversity, are under exploration; however, more work needs to be done to further validate clinically useful predictive biomarkers . Without the identification of such reliable and granular predictive tools, clinicians are left to use more blunt prognostic tools, such as the ECOG PS, to guide practice.…”

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches

“…Based on the above mechanism, the outcome of anti‐PD‐1/PD‐L1 immunotherapy should be predicted by tumour neoantigen level, the level of tumour infiltrating lymphocytes (TILs) and cancer/TME PD‐L1 expression. While there are positive correlations of these factors to anti‐PD‐1/PD‐L1 immunotherapy sensitivity in many studies, the associations are not always strong or significant . The response of PD1/PD‐L1 negative tumours to checkpoint inhibitors was unexpected.…”

“…For details please read the review article by Boussiotis . The anti‐PD‐1 and anti‐PD‐L1 inhibitors are antibodies which specifically bind to PD‐1 on T cell and PD‐L1 on cancer or TME cells respectively to prevent the interaction of PD‐1 and PD‐L1, consequently reactivate the anti‐tumour immune response of cytotoxic T‐cells (Figure ).…”

“…The mechanisms of BCG‐induced tumour‐specific immunity have been extensively investigated, although many unclear issues remain . Only 25% advanced/metastatic bladder cancers respond to anti‐PD‐1/PD‐L1 ICB , thus further improvement is required. As previous reviews have focused on either BCG or anti‐PD‐1/PD‐L1 immunotherapies, rarely both, here we review bladder cancer BCG and anti‐PD1/PD‐L1 immunotherapies together to explore our knowledge and the potential to improve immunotherapy.…”

Toll‐like receptors: The role in bladder cancer development, progression and immunotherapy

“…ICI has recently became one of the favourable advances in treatment of urothelial cancer with five agents targeting the PD‐1/PD‐L1 being recently approved by the US FDA. Several clinical trials are ongoing in various disease settings, employing these agents …”