TY - JOUR
T1 - Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma
AU - Duffy, Austin G.
AU - Ulahannan, Susanna V.
AU - Makorova-Rusher, Oxana
AU - Rahma, Osama
AU - Wedemeyer, Heiner
AU - Pratt, Drew
AU - Davis, Jeremy L.
AU - Hughes, Marybeth S.
AU - Heller, Theo
AU - ElGindi, Mei
AU - Uppala, Ashish
AU - Korangy, Firouzeh
AU - Kleiner, David E.
AU - Figg, William D.
AU - Venzon, David
AU - Steinberg, Seth M.
AU - Venkatesan, Aradhana M.
AU - Krishnasamy, Venkatesh
AU - Abi-Jaoudeh, Nadine
AU - Levy, Elliot
AU - Wood, Brad J.
AU - Greten, Tim F.
N1 - Publisher Copyright:
© 2016
PY - 2017/3/1
Y1 - 2017/3/1
N2 - 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.
AB - 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.
KW - Hepatocellular carcinoma
KW - Immune
KW - Immune checkpoint
KW - Liver cirrhosis
KW - T-Lymphocytes
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U2 - 10.1016/j.jhep.2016.10.029
DO - 10.1016/j.jhep.2016.10.029
M3 - Article
C2 - 27816492
AN - SCOPUS:85007494451
SN - 0168-8278
VL - 66
SP - 545
EP - 551
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -