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Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation
  1. Barbara Behm1,
  2. Pietro Di Fazio2,
  3. Patrick Michl3,
  4. Daniel Neureiter4,
  5. Ralf Kemmerling4,
  6. Eckhart Georg Hahn1,
  7. Deike Strobel1,
  8. Thomas Gress3,
  9. Detlef Schuppan5,6,
  10. Thaddaeus Till Wissniowski1,3
  1. 1Department of Medicine 1, University Hospital Erlangen-Nuremberg, Erlangen, Germany
  2. 2Institute for Surgical Research, Philipps-University Marburg, Marburg, Germany
  3. 3Division of Gastroenterology, University Hospital, Philipps-University Marburg, Marburg, Germany
  4. 4Institute of Pathology, Paracelsus Medical University, Salzburg, Austria
  5. 5Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Institute of Translational Immunology, University Medical Center, Mainz, Germany
  1. Correspondence to Dr Thaddaeus Till Wissniowski, Division of Gastroenterology, University Hospital Marburg, Baldingerstraße, Marburg 35043, Germany; Wissniowski{at}icloud.com

Abstract

Introduction Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma.

Methods Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor α, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon γ, and vascular endothelial growth factor were measured in serum.

Results Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16-fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls.

Conclusions The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer.

  • IMMUNOTHERAPY
  • CANCER
  • HEPATIC METASTASES
  • HEPATOCELLULAR CARCINOMA
  • INTERVENTIONAL RADIOLOGY

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