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Checkpoint Inhibitors Herald a New Era for Treating Urothelial Cancer

Matthew D. Galsky, MD
Published: Tuesday, Nov 07, 2017
Matthew Galsky, MD

Matthew Galsky, MD
Metastatic urothelial cancer (UC) is a relatively chemotherapy-sensitive malignancy. With contemporary cisplatin-based combination chemotherapy regimens, objective responses are achieved in approximately 50% to 60% of patients and complete radiographic responses are achieved in approximately 10% to 20% of patients.1 Unfortunately, response durations are typically short, with only 5% to 10% of patients achieving durable disease control. Decades of clinical trials exploring modifications of cytotoxic regimens, including the use of different or more drugs, demonstrated that a therapeutic plateau had been reached with conventional chemotherapeutic agents, highlighting the need for novel approaches.

Instead of a dysfunctional immune system as a general explanation of the lack of effective anticancer immune responses in patients with cancer, it is now understood that in at least a subset of patients, these immune checkpoints are co-opted by cancers to dampen antitumor immunity. Data in model systems, and in patients, now demonstrate that the administration of blocking antibodies to these checkpoints can overcome such adaptive immune resistance.

Clinical Experience With Single-Agent Immune Checkpoint Blockade in UC

Anti-CTLA-4 antibodies were the first immune checkpoint inhibitors to be widely explored in cancer, and ipilimumab (Yervoy) is approved for the treatment of metastatic melanoma by the FDA. Studies in syngeneic mouse model systems of bladder cancer have demonstrated anticancer activity, providing a rationale for clinical testing of CTLA-4 blockade.3 Despite such data, there have been very few completed clinical trials exploring CLTA-4 blockade in UC. Bradley C. Carthon, MD, PhD, and colleagues performed a “window of opportunity” study of pre-cystectomy ipilimumab in patients with invasive UC of the bladder as a means to study the pharmacodynamic effects of treatment; that is, the investigators compared changes in the immune microenvironment in the posttreatment cystectomy specimens with the pretreatment transuretheral resection specimens.4 Interestingly, in this study of 12 patients treated with 2 doses of ipilimumab prior to cystectomy, patients receiving a higher dose of ipilimumab demonstrated a robust infiltration of T cells in the posttreatment cystectomy specimen.
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