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Br J Cancer. 2015;113(12):1666-76.

A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma.

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제1저자 이정훈 · 교신저자 김윤준

PMID 26657650 PMC4702003 DOI 10.1038/bjc.2015.430 IF 7.8 소화기내과
소속 (5)
  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Republic of Korea.
  2. Division of DC Cancer Vaccine, JW CreaGene Research Institute, JW CreaGene Inc., Seongnam-si, Gyeonggi-do, 162-120, Republic of Korea.
  3. Department of Biological Science, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Republic of Korea.
  4. Cancer Center, Samsung Medical Center, School of Medicine, Sungkyunkwan University, Ilwon-dong, Kangnam-gu, Seoul, 135-710, Republic of Korea.
  5. Department of Surgery, Seoul National University College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.

Abstract

BACKGROUND To date, no adjuvant treatment has been shown to have a clear benefit in patients with hepatocellular carcinoma (HCC). In this prospective phase I/IIa study, we evaluated the safety and efficacy of adjuvant dendritic cell (DC) therapy in HCC patients who received primary treatment for HCC.

METHODS Twelve HCC patients who had no viable tumour after primary treatments were included. Dendritic cell vaccines pulsed with cytoplasmic transduction peptide-attached alpha-fetoprotein, glypican-3 and melanoma-associated antigen 1 recombinant fusion proteins were injected subcutaneously near to inguinal lymph nodes. Adverse effects, time to progression (TTP), and associated immune responses were evaluated after DC vaccination.

RESULTS Nine of 12 patients had no tumour recurrence up to 24 weeks after DC vaccination. Among a total of 144 adverse events, 129 events (89.6%) were regarded as adverse drug reactions, all of which were grade 1 or 2. The majority of patients showed enhanced anti-tumour immune responses after DC vaccination. Recurrence-free patients exhibited relatively stronger anti-tumour immune responses than patients who developed recurrence after DC vaccination, as evidenced by lymphocyte proliferation and IFN-γ ELISPOT assays. The median time of TTP was 36.6 months in the DC-vaccination group and 11.8 months in the control group (hazard ratio, 0.41; 95% confidence interval, 0.18-0.95; P=0.0031 by log-rank test).

CONCLUSIONS Adjuvant DC vaccine for HCC was safe and well tolerated in phase I/IIa study, and preliminary efficacy data are encouraging to warrant further clinical study in patients with HCC after primary treatments.

Figures

Figure 1
Figure 1 Study design. (A) Study design for vaccination and evaluation. CT=computed tomography; MRI=magnetic resonance imaging; DC=dendritic cell. (B) Flow chart for tolerated dose-finding study. DLT=dose-limiting toxicity; TD=tolerated dose.
Figure 2
Figure 2 Surface phenotypes and T-cell stimulation capacity of TAA-pulsed mDCs in the preclinical study, which were performed as described in the Supplementary Method. (A) Representative FACS data (left) and statistical analysis (right) of the surface phenotype of imDCs and TAA-pulsed mDCs. (B) CD8+ T-cell population (left) and the levels of IFN-γ and IL-4 (right) were assessed from the co-culture of autologous T cells with TAA-pulsed or Ag-unpulsed mDCs at a 10 : 1 ratio in the presence of IL-7 (Peprotech). Activated T cells were restimulated three times every 7–8 days with a same set of TAA-pulsed DCs at the same ratio as described in the Supplementary Method. (C) From the activated T cells, the CTL was assessed with MHC-matched HepG2 target cells at different effector/target (E/T) ratios as described in the Supplementary Method. Data are presented as mean±s.d. of nine samples pooled from three individual experiments. *P<0.05 and **P<0.01 compared with control CTLs prepared by stimulation of T cells with Ag-unpulsed mDCs, Student's t-test.
Figure 3
Figure 3 Immunological analysis after DC vaccination. (A) Antigen-specific lymphocyte proliferation assay was performed during and after DC vaccinations using the autologous PBMCs obtained from 12 patients (upper), and the results were further analysed in recurrence-free patients (lower left) and recurrent patients (lower right). The proliferation was determined by 3H-thymidine incorporation (dpm) using a liquid scintillation counter. Data are presented as mean±s.e., *P<0.05. (B) ELISPOT assay was performed with the PBMCs obtained from each patient at the indicated time points after the start of DC vaccination. The results from all (12) patients (upper), the nine recurrence-free patients (lower left) and the three recurrent patients (lower right) are presented as mean±s.e.
Figure 4
Figure 4 CT and MRI scan data of two representative patients (pt4 and pt6) before and after one cycle of antigen-pulsed DC vaccination. Treatment records of each patient are summarised.
Figure 5
Figure 5 TTP and RFS (starting from primary treatments rather than baseline radiographic tumour assessments) of patients treated with DC vaccine during the trial period and 4-year follow-up study in comparison with historical controls (n=31). The composition of 31 patients with HCC for historical control group was summarised in Table 5. A statistically significant difference in survival was noted (P<0.05).

그림 출처: PubMed Central 공개 논문 (PMC4702003)

Conflict of interest statement

YL, MKHeo, and J-SS are CreaGene Inc. employees. Y-SB has been a consultant for JW CreaGene Inc. All remaining authors have declared no conflicts of interest.

그 밖의 정보
출판 형태
Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't
저널
British journal of cancer · eISSN 1532-1827
전자 출판
2015-12-10
MeSH
Aged · Antigens, Neoplasm / immunology · Carcinoma, Hepatocellular / therapy · Cell Transplantation* · Dendritic Cells / immunology · Female · Humans · Immunotherapy* · Liver Neoplasms / therapy · Male · Middle Aged · Treatment Outcome
Substances
Antigens, Neoplasm
참고문헌
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