Austin G Duffy1, Susanna V Ulahannan1, Oxana Makorova-Rusher1, Osama Rahma1, Heiner Wedemeyer2, Drew Pratt3, Jeremy L Davis4, Marybeth S Hughes4, Theo Heller5, Mei ElGindi1, Ashish Uppala1, Firouzeh Korangy1, David E Kleiner3, William D Figg6, David Venzon7, Seth M Steinberg7, Aradhana M Venkatesan8, Venkatesh Krishnasamy8, Nadine Abi-Jaoudeh8, Elliot Levy8, Brad J Wood8, Tim F Greten9. 1. Gastrointestinal Malignancies Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. 2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. 3. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. 4. Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. 5. Translational Hepatology Unit, Liver Diseases Branch (LDB), National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) National Institutes of Health, USA. 6. Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. 7. Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, USA. 8. Center for Interventional Oncology, Radiology and Imaging Sciences and Center for Cancer Research, National Institutes of Health, USA. 9. 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.
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 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. 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 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). 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. Published by Elsevier B.V.
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 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. 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 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). 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. Published by Elsevier B.V.
Authors: Martijn H M G M den Brok; Roger P M Sutmuller; Stefan Nierkens; Erik J Bennink; Liza W J Toonen; Carl G Figdor; Theo J M Ruers; Gosse J Adema Journal: Cancer Res Date: 2006-07-15 Impact factor: 12.701
Authors: Erik E Johnson; Brett H Yamane; Ilia N Buhtoiarov; Hillary D Lum; Alexander L Rakhmilevich; David M Mahvi; Stephen D Gillies; Paul M Sondel Journal: Clin Cancer Res Date: 2009-07-28 Impact factor: 12.531
Authors: Josep M Llovet; Sergio Ricci; Vincenzo Mazzaferro; Philip Hilgard; Edward Gane; Jean-Frédéric Blanc; Andre Cosme de Oliveira; Armando Santoro; Jean-Luc Raoul; Alejandro Forner; Myron Schwartz; Camillo Porta; Stefan Zeuzem; Luigi Bolondi; Tim F Greten; Peter R Galle; Jean-François Seitz; Ivan Borbath; Dieter Häussinger; Tom Giannaris; Minghua Shan; Marius Moscovici; Dimitris Voliotis; Jordi Bruix Journal: N Engl J Med Date: 2008-07-24 Impact factor: 91.245
Authors: Zachary J Brown; Su Jong Yu; Bernd Heinrich; Chi Ma; Qiong Fu; Milan Sandhu; David Agdashian; Qianfei Zhang; Firouzeh Korangy; Tim F Greten Journal: Cancer Immunol Immunother Date: 2018-06-29 Impact factor: 6.968
Authors: Changqing Xie; Austin G Duffy; Donna Mabry-Hrones; Bradford Wood; Elliot Levy; Venkatesh Krishnasamy; Javed Khan; Jun S Wei; David Agdashian; Manoj Tyagi; Vineela Gangalapudi; Suzanne Fioravanti; Melissa Walker; Victoria Anderson; David Venzon; William D Figg; Milan Sandhu; David E Kleiner; Maria Pia Morelli; Charalampos S Floudas; Gagandeep Brar; Seth M Steinberg; Firouzeh Korangy; Tim F Greten Journal: Hepatology Date: 2019-03-10 Impact factor: 17.425