Review
PD-1/PD-L1 Combinations in Advanced Urothelial Cancer: Rationale and Current Clinical Trials

https://doi.org/10.1016/j.clgc.2019.03.009Get rights and content

Abstract

Chemotherapy is no longer the only viable option for patients with locally advanced or metastatic urothelial carcinoma. Immunotherapy, as checkpoint inhibition, has received United States Food and Drug Administration approval in the preceding several years, both in the second-line and first-line for cisplatin-ineligible patients. Those who respond often do so durably; however, response rates in the first line are 23% to 24%, and are lower in the second line. With a focus on urothelial carcinoma, this review discusses the tumor microenvironment and its negative influence on anti-tumor immunity, as well as measures to counteract immune suppression or evasion. The review then describes a range of current clinical trials implementing these measures in the form of programmed death-combination therapy, specifically in advanced bladder and urothelial cancers.

Section snippets

Epidemiology of Bladder Cancer

Worldwide, bladder cancer (BC) is the ninth most common cancer. Urothelial carcinoma (UC) is the predominant (90%) histologic subtype. This histology can occur throughout the urinary tract, but is most frequently found in the bladder.1 In 2012, 429,800 new cases of BC arose, with the highest incidences in Western Europe and Northern America.2, 3 Within that year, there were 165,100 deaths attributed to the disease.2 Focusing on the United States in 2018, BC will be newly diagnosed in 81,190

Recent Advancements in UC Immunotherapy

Immune checkpoints function to induce immune self-tolerance. T-cell effector activity must be tightly regulated to prevent self-damage from physiologic defensive responses and the induction of autoimmunity. Many immune checkpoints are known to exist; however, the majority of research and clinical implementation has been focused on antagonists of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and the programmed death receptor (PD-1) and programmed death receptor ligand (PD-L1).7 Although

Reversal of T-cell Exhaustion

Chronic antigen stimulation in the absence of co-stimulatory signals “exhausts” effector cells.44 As the presence and severity of exhaustion are correlated with surface presentation of inhibitory receptors, and is in large part attributed to their signaling, reversal of exhaustion would entail blocking these receptors. PD blockade in lymphocytic choriomeningitis virus infection models rescues anti-viral immunity,45 and PD inhibition has shown efficacy in multiple tumor types. Although

Combined Chemotherapy and ICI

Rather than T-cell suppression, immune inaction can result from immune ignorance. Tumors not presenting immunogenic antigen, named cold tumors, may pass as “self.” Generating a response to PD blockade, then, would entail manufacturing exposure of antigen to the immune system. Chemotherapy is a potential method, yet it causes a range of host toxicities, including a weakened immune system. Synergy in concurrent chemo- and immunotherapy may be seem counterintuitive. CTLA-4 inhibition (ipilimumab)

Conclusion

In the treatment of advanced UC, CI has produced outcomes that compare with or improve on those of platinum-based chemotherapy. The durability of response is a particular advantage for CI. Significant responses, however, occur in a minority of patients, leaving anti-tumor immunity untapped in the majority. Growing understanding of the TME and its diversity among cancers and among patients will provide information on the likelihood of immunotherapy success. Furthermore, this understanding will

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

This research is supported in part by the New York University Clinical and Translational Science Award grant UL1 TR001445, from the National Center for Advancing Translational Sciences, National Institutes of Health.

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