Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes

Abstract

Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer. Overall, these agents have shown objective response rates of around 20% to 23%, which indicates that a significant proportion of patients do not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement in the median duration of response compared with chemotherapy, still only half of the patients develop long-term maintained remissions. Active research is ongoing in several fields, aiming to increase the number of patients that benefit from ICI, and this research is largely based on the development of biomarkers for personalized immunotherapy and novel combinations of ICI with other agents. This article will review ongoing efforts to develop combinations of ICI with other therapeutic strategies in patients with urothelial cancer, including chemotherapy, targeted agents, other immunotherapy strategies, and radiotherapy.

Pretreatment Blood Parameters Predict Efficacy from Immunotherapy Agents in Early Phase Clinical Trials

“…The introduction of ICIs‐based immunotherapy represented a real breakthrough for the treatment of cancer, changing the therapeutic algorithms of several tumors [17–23]. However, this transformative effect was limited to small number of patients and was much less evident in some other malignancies, including breast cancer and microsatellite stable colorectal cancer [39–41].…”

“…Monoclonal antibodies targeting cytotoxic T‐lymphocyte–associated antigen‐4, programmed cell death protein‐1 (PD‐1), and PD‐ligand 1 (PD‐L1), also defined as immune checkpoint inhibitors (ICIs), revolutionized the treatment of several solid tumors [17–23]. However, the efficacy of ICIs is limited to a small proportion of patients, and, at present, no validated and reliable predictive biomarkers of response or resistance to immunotherapy have been identified.…”

Intratumoral CCR5 + neutrophils identify immunogenic subtype muscle-invasive bladder cancer with favorable prognosis and therapeutic responses

“… 2 Immune checkpoint inhibitors (ICIs) represent an exciting advancement over previous standard treatments for advanced or metastatic UC. 3 However, the overall objective response rates (ORRs) of five ICIs targeting PD-1 or PD-L1 were relatively low (< 30%). 4 , 5 Therefore, urgent works including better understanding of the underlying the complex mechanisms of UC immune microenvironment and precise stratification for patients who might have better adjuvant chemotherapy (ACT) response and ICIs response are posed at the forefront desk of the clinical cancer research.…”

Galectins in prostate and bladder cancer: tumorigenic roles and clinical opportunities

“…In this setting, radical cystectomy preceded by neoadjuvant chemotherapy is considered the standard therapy in patients deemed fit, although researchers and clinicians are now also considering bladder-sparing approaches 23 . The advent of immunotherapy with ICIs has been a major breakthrough in bladder cancer and has become a new standard of care for patients with metastatic disease in the second line setting 15 and a valid option in the first-line setting for patients with programmed cell death 1 ligand 1 (PD-L1)-positive metastatic disease who are ineligible for cisplatin 24 . In addition, ICIs are currently being tested in clinical trials in localized disease (NMIBC and MIBC) and in combination with chemotherapy in the metastatic first-line setting 24 .…”