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New Evidence Supports a Key Role of the Immune System in HCC

Published Online: Sep 19,2016
A further analysis of patients from the CheckMate-040 study with 3 years of follow-up was also presented at the 2016 ASCO Annual Meeting by Anthony El-Khoueiry, MD, phase I program director at the University of Southern California Norris Comprehensive Cancer Center, and colleagues.7

Eligible patients had a Child-Pugh Score ≤7 and had previously failed or were intolerant of sorafenib. Nivolumab dosing ranged from 0.1 to 10 mg/kg for up to 2 years. The primary endpoint was safety, and secondary endpoints were antitumor activity and duration of response. Among the 51 patients who were enrolled and treated with nivolumab, 73% had prior sorafenib therapy, 76% had extrahepatic metastasis, and 12% had vascular invasion. Most discontinuations (35/41) were due to progressive disease.

Nivolumab treatment exhibited durable responses and disease stabilization across all dosages and cohorts. The median duration of response was 23.7 months, and median OS was 15.1 months. The OS rates at 6, 9, 12, and 18 months were 67%, 67%, 59%, and 48%, respectively. The complete response (CR) and partial response (PR) rates were 6% and 8%, respectively. Half of patients achieved stable disease.

Nivolumab exhibited a manageable safety profile. Treatment-related AEs occurred in 77% of patients, most commonly rash and AST increase (20% each). Grade 3/4 trAEs occurred in 20% of patients, most commonly increases in AST (10%), lipase (6%), or ALT (6%). The maximum tolerated dose was not reached.

“Hepatocellular carcinoma is an aggressive and fatal cancer, comprising 90% of all liver cancer in adults worldwide with limited therapeutic options for patients with advanced stage disease; no treatment advances have been made for patients who fail to respond or progress on the current standard of care,” said El-Khoueiry in a press release.8 “These preliminary data are encouraging and support the ongoing evaluation of nivolumab in this patient population, as they show promising preliminary survival data, and durable partial or complete response in one out of five nivolumab-treated patients, with many others experiencing stable disease.”

A randomized phase III study, CheckMate-459, is currently recruiting participants and will evaluate nivolumab as a first-line therapy in patients with advanced HCC (NCT02576509). In the open-label study, the efficacy of nivolumab will be compared with sorafenib. Eligible patients have 1 or more lesions, Child-Pugh class A liver function, ECOG status of 0 or 1, and no prior systemic therapy.

Over 700 patients will be randomized in a 1:1 ratio to receive nivolumab or sorafenib until disease progression or unacceptable toxicity. The primary objectives are time to progression and OS. The secondary endpoints are ORR, PFS, and PD-L1 expression. Patient data will be stratified by vascular invasion and/or extrahepatic spread, etiology, and geography. The estimated primary completion date is July 2017.

Vaccine Therapy Under Exploration for HCC

Other novel approaches are also being explored that target immunoregulatory cells, with one such trial exploring a vaccine therapy in combination with sorafenib. In a case study reported by Yongxiang Yi et al in Molecular Clinical Oncology,9 a patient with metastatic HCC achieved a CR after treatment with sorafenib, focused ultrasound knife therapy, and dendritic cell (DC) DRibbles vaccine.

DRibbles are autophagosomes containing a variety of antigens from antigen donor cells. They stimulate antigen-specific CD8 T cells ex vivo and induce a T-cell response against HCC in vivo. The case report described a 42-year-old male with HBV-associated HCC. The patient underwent curative resection, but in less than 2 months after surgery, multiple intrahepatic and extrahepatic lesions were detected, and the patient was treated with sorafenib. Because alpha-fetoprotein (AFP) levels continued to rise, focused ultrasound knife therapy was initiated, as was DC-DRibbles therapy.

Eight months after combination therapy, AFP levels returned to normal and remission of the liver and lung metastases was observed. Two years after the combination treatment, metastatic lesions were undetectable by computed tomography (CT) scan. No serious AEs were reported.

“Our results demonstrated that antigen-specific T-cell response aimed to treat recurrent HCC may be induced through stimulation by the DC-DRibbles vaccine,” the authors concluded. The case supports a combination strategy for patients with recurrent HCC after resection.

An ongoing, open-label, phase II trial will investigate the safety and efficacy of the individualized anticancer vaccine CRCL-AlloVax in approximately 30 patients with advanced HCC after prior sorafenib therapy (NCT02409524).

The novel AlloVax therapy is a vaccine consisting of chaperone-rich cell lysate (CRCL) antigens, derived from a patient’s own tumor cells, in combination with AlloStim cells, which are activated allogenic Th1 memory T cells that contain cytolytic granules.10 The primary outcome measure is survival compared with historical controls. The estimated primary completion date is July 2017.

In conclusion, recent studies support the vital importance of immunosuppression in HCC and key molecular components that contribute to hepatocarcinogenesis. While novel immunomodulatory therapies are on the horizon, sorafenib may reduce the immunosuppressive network in HCC. Further work is needed to fully capitalize on the immune system as an anticancer therapy for HCC.

  1. Tumanov AV, Koroleva EP, Christiansen PA, et al. T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology. 2009;136(2):694-704.e4.
  2. Wolf MJ, Adili A, Piotrowitz K, et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 2014;26(4):549-564.
  3. Endig J, Buitrago-Molina LE, Marhenke S, et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell. 2016;30(2):308-323.
  4. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454.
  5. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134-144.
  6. El-Khoueiry A, Sangro B, Yau T, et al. Phase I/II safety and antitumor activity of nivolumab (nivo) in patients (pts) with advanced hepatocellular carcinoma (HCC): Interim analysis of the CheckMate-040 dose escalation study. J Clin Oncol. 2016;34(suppl; abstr 4012).
  7. Bristol-Meyers Squibb. Phase I/II Opdivo (nivolumab) Trial Shows Bristol-Myers Squibb’s PD-1 Immune Checkpoint Inhibitor is First to Demonstrate Anti-Tumor Activity In Patients With Hepatocellular Carcinoma [press release]. May 29, 2015.http://news.bms.com/press-release/phase-iii-opdivo-nivolumab-trial-shows-bristol-myers-squibbs-pd-1-immune-checkpoint-in. Accessed August 21, 2016.
  8. Yi Y, Han J, Fang Y, et al. Sorafenib and a novel immune therapy in lung metastasis from hepatocellular carcinoma following hepatectomy: a case report. Mol Clin Oncol. 2016;5(2):337-341. 
  9. Immunovative Therapies Ltd. http://www.immunovative.com. Accessed August 15, 2016.

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New Evidence Supports a Key Role of the Immune System in HCC
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