Addition of a dendritic cell vaccine to conditioning cyclophosphamide and chemoembolisation to prolong progression-free survival in patients with hepatocellular carcinoma: the ImmunoTACE RCT

Background A previous study by our group using dendritic cells pulsed ex vivo with the lysate of the HepG2 cell line showed clinical benefit with evidence of antigen-specific T-cell responses in some patients with advanced hepatocellular carcinoma. This trial set out to investigate the activity of this vaccine in combination with chemoembolisation compared to chemoembolisation alone in patients with intermediate stage hepatocellular carcinoma. All patients also received a conditioning regimen comprising low-dose cyclophosphamide. Objectives To determine whether the addition of a dendritic cell vaccine to chemoembolisation and preconditioning cyclophosphamide prolongs progression-free survival and warrants further investigation. Design Multicentre, open-label, randomised Phase II trial. Setting Three tertiary referral units in the United Kingdom: Queen Elizabeth Hospital, Birmingham; Aintree University Hospital/Clatterbridge Cancer Centre, Liverpool and Queen’s Medical Centre, Nottingham. Participants Patients > 18 years with intermediate stage hepatocellular carcinoma, performance status 0–2 and Child–Pugh A/B7 liver function. Intervention Preconditioning cyclophosphamide on Day 1 and Day 29 followed by chemoembolisation on Day 31 (± dendritic cell infusion), followed by further preconditioning cyclophosphamide on Days 60, 90 and 120 (± additional dendritic cell infusions on Days 62, 92 and 122). Main outcome measures The primary endpoint was progression-free survival time using Response Evaluation Criteria in Solid Tumours v1.1 criteria. Secondary endpoints were progression-free survival time based on modified (m) Response Evaluable Criteria in Solid Tumours criteria, overall survival time, radiological response according to Response Evaluable Criteria in Solid Tumours 1.1 criteria, radiological response based on Modified Response Evaluable Criteria in Solid Tumours criteria, change in the serum alpha-fetoprotein tumour marker, toxicity using Common Terminology Criteria for Adverse Events v4.0 and immune response. Results Between March 2016 and October 2019, 55 patients were randomised of whom 48 are evaluable (24 in each group). The progression-free survival time using Response Evaluable Criteria in Solid Tumours criteria was 18.6 months in patients treated with chemoembolisation plus preconditioning cyclophosphamide plus dendritic cell infusions (Group 2) compared to 10.4 months in those treated with chemoembolisation plus preconditioning cyclophosphamide alone (Group 1) (hazard ratio 0.43, upper value of one-sided 80% confidence interval 0.57; p = 0.016). Although not statistically powered, the progression-free survival time using Modified Response Evaluable Criteria in Solid Tumours criteria showed a similar magnitude of benefit (18.6 vs 10.8 months: hazard ratio 0.48, 95% confidence interval 0.22 to 1.02). The overall response rate (complete response and partial response) by Response Evaluable Criteria in Solid Tumours was 54% in Group 2 and 29% in Group 1 and the disease control rate (complete response, partial response and stable disease) was 92% in Group 2 and 67% in Group 1. Treatment with dendritic cell vaccination was associated with an enhanced antigen-specific immune response. Treatment was well tolerated with few additional adverse events from the additional dendritic cell infusions. Conclusions Chemoembolisation plus preconditioning cyclophosphamide plus dendritic cell infusions merit further investigation in a randomised Phase III trial but the trial design will need to take into account the current evolving hepatocellular carcinoma treatment landscape. Limitations The current dendritic cell manufacturing process limits large-scale use and further validation and automation of the process will be needed prior to testing in a randomised Phase III trial. Future Work Further testing in a randomised Phase III trial is warranted. Trial registration This trial is registered as ISRCTN11889464; EudraCT number: 2011-001690-62. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 09/160/24) and is published in full in Efficacy and Mechanism Evaluation ; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information.