Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma

Austin G. Duffy, Susanna V. Ulahannan, Oxana Makorova-Rusher, Osama Rahma, Heiner Wedemeyer, Drew Pratt, Jeremy L. Davis, Marybeth S. Hughes, Theo Heller, Mei ElGindi, Ashish Uppala, Firouzeh Korangy, David E. Kleiner, William D. Figg, David Venzon, Seth M. Steinberg, Aradhana M. Venkatesan, Venkatesh Krishnasamy, Nadine Abi-Jaoudeh, Elliot LevyBrad J. Wood, Tim F. Greten*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

629 Scopus citations

Abstract

Background & Aims Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Methods Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10 mg/kg i.v.) every 4 weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8 weeks. Results No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1–51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4 months (95% CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95% CI 9.3 to 15.4 months). Conclusions Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Lay summary Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. Clinical trial number ClinicalTrials.gov: NCT01853618.

Original languageEnglish
Pages (from-to)545-551
Number of pages7
JournalJournal of Hepatology
Volume66
Issue number3
DOIs
StatePublished - 1 Mar 2017
Externally publishedYes

Keywords

  • Hepatocellular carcinoma
  • Immune
  • Immune checkpoint
  • Liver cirrhosis
  • T-Lymphocytes

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