New progress and clinical research translation of immune checkpoint inhibitors in systemic therapy of gallbladder cancer

Abstract

Gallbladder cancer (GBC) is a highly malignant tumor of the biliary tract system.Although it is less common than other malignant tumors of the digestive system, its incidence and mortality rates have been on a continuous rise. With insidious early symptoms, the majority of patients are diagnosed at an advanced stage when the disease is detected. Surgical resection remains the radical treatment for gallbladder cancer yet many patients lose the opportunity for surgical intervention when seeking medical attention due to the onset of symptoms.In addition, given the high invasiveness and high recurrence rate of gallbladder cancer, systemic therapy beyond surgical treatment is particularly crucial. In recent years, precision medicine centered on immunotherapy and targeted therapy has exhibited certain therapeutic effects and improved the quality of life in patients with advanced cancer. Immunotherapy is a therapeutic modality that prevents immune evasion of tumor cells, primarily by means of immune checkpoint inhibitors such as CTLA-4 and PD- 1/PD-L1 inhibitors, among which PD-1/PD-L1 inhibitors are widely used in the immunotherapy of gallbladder cancer.Following the success of the global Phase III TOPAZ- 1 and KEYNOTE-966 trials, durvalumab in combination with gemcitabine and cisplatin, as well as pembrolizumab combined with gemcitabine and cisplatin, have been approved in multiple countries and recommended by authoritative guidelines as the preferred first-line systemic therapeutic regimens for advanced biliary tract cancers. A number of clinical trials conducted in recent years have initiated subgroup analyses of biliary tract cancer together with detections of biomarkers and the tumor microenvironment, providing guidance for immunotherapy of gallbladder cancer. This article elaborates on the mechanisms of immune checkpoint inhibitors, the unique tumor microenvironment and biomarkers specific to gallbladder cancer, summarizes clinical trials concerning gallbladder cancer and those incorporating gallbladder cancer subgroup analyses, interprets authoritative clinical guidelines and relevant policies, and presents the strategies and procedures adopted by our team for administering immunotherapy to patients with gallbladder cancer in routine clinical practice.