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Hepatology. 2019 May;69(5):2048-2060. doi: 10.1002/hep.30482. Epub 2019 Mar 10.

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer.

Author information

1
Hematology/Oncology Fellowship Program, National Heart, Lung, and Blood Institute/National Cancer Institute, National Institutes of Health, Bethesda, MD.
2
Gastrointestinal Malignancies Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
3
Radiology and Imaging Sciences, Center for Cancer Research, National Institutes of Health, Bethesda, MD.
4
Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD.
5
Biostatistics and Data Management Section, NCI, NIH, Bethesda, MD.
6
Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
7
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
8
Biostatistics and Data Management Section, Center for Cancer Research, National Institutes of Health, Bethesda, MD.
9
NCI CCR Liver Cancer Program, Bethesda, MD.

Abstract

Treatment options for patients with advanced biliary tract cancer are limited. Dysregulation of the immune system plays an important role in the pathogenesis of biliary tract cancer (BTC). This study aimed to investigate whether tremelimumab, an anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor, could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC. Patients were enrolled to receive monthly tremelimumab (10 mg/kg, intravenously) for six doses, followed by infusions every 3 months until off-treatment criteria were met. Thirty-six days after the first tremelimumab dose, patients underwent subtotal microwave ablation. Interval imaging studies were performed every 8 weeks. Adverse events (AEs) were noted and managed. Tumor and peripheral blood samples were collected to perform immune monitoring and whole-exome sequencing (WES). Twenty patients with refractory BTC were enrolled (median age, 56.5 years). No dose-limiting toxicities were encountered. The common treatment-related AEs included lymphopenia, diarrhea, and elevated transaminases. Among 16 patients evaluable for efficacy analysis, 2 (12.5%) patients achieved a confirmed partial response (lasting for 8.0 and 18.1 months, respectively) and 5 patients (31.3%) achieved stable disease. Median progression free survival (PFS) and overall survival (OS) were 3.4 months (95% confidence interval [CI], 2.5-5.2) and 6.0 months (95% CI, 3.8-8.8), respectively. Peripheral blood immune cell subset profiling showed increased circulating activated human leukocyte antigen, DR isotype ([HLA-DR] positive) CD8+ T cells. T-cell receptor (TCR)β screening showed tremelimumab expanded TCR repertoire, but not reaching statistical significance (P = 0.057). Conclusion: Tremelimumab in combination with tumor ablation is a potential treatment strategy for patients with advanced BTC. Increased circulating activated CD8+ T cells and TCR repertoire expansion induced by tremelimumab may contribute to treatment benefit.

PMID:
30578687
PMCID:
PMC6461476
[Available on 2020-05-01]
DOI:
10.1002/hep.30482

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