Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
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.



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 10mg/kg i.v.) every 4weeks 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 8weeks.



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 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months).



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.



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.



ClinicalTrials.gov: NCT01853618.
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Austin G
AG
Duffy
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Susanna V
SV
Ulahannan
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Oxana
O
Makorova-Rusher
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Osama
O
Rahma
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
Heiner
H
Wedemeyer
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Drew
D
Pratt
Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Jeremy L
JL
Davis
Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Marybeth S
MS
Hughes
Translational Hepatology Unit, Liver Diseases Branch (LDB), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) National Institutes of Health, USA.
Theo
T
Heller
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Mei
M
ElGindi
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Ashish
A
Uppala
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Firouzeh
F
Korangy
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
David E
DE
Kleiner
Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
William D
WD
Figg
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
David
D
Venzon
Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA.
Seth M
SM
Steinberg
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA.
Aradhana M
AM
Venkatesan
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA.
Venkatesh
V
Krishnasamy
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA.
Nadine
N
Abi-Jaoudeh
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA.
Elliot
E
Levy
Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA.
Brad J
BJ
Wood
Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. Electronic address: tim.greten@nih.gov.
Tim F
TF
Greten
D055011:Ablation Techniques; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C520704:tremelimumab
Hepatocellular carcinoma; Immune; Immune checkpoint; Liver cirrhosis; T-Lymphocytes