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. 2022 Sep 8;14(18):4380. doi: 10.3390/cancers14184380

Table 2.

Summary of clinical trials regarding DC-vaccine-based combination immunotherapy for treating HCC patients.

Treatment Disease Stage Targeted Clinical Trial Identifier Start Year Patient Number Phase Status Clinical Results Publication
Combination of DC Vaccines and Anticancer Therapies
Immature-DC vaccine combined with EBRT Advanced primary HCC NA 2001 12 I Completed

  • Safe and well tolerated

  • 16.7% of patients with PR

  • 25% of patients with decreased serum levels of AFP

 Chi et al. [39]
Mature-DC vaccine combined with EBRT Unresectable primary HCC, AJCC TNM (8th edition) stage IIIA to IVB, Child–Pugh class A NCT03942328 2019 26 Early I Ongoing NA NA
Mature-DC vaccine combined with RFA HCV-related primary HCC JPRN-C000000451 2006 5 NA Completed NA NA
OK432-stimulated mature-DC vaccine combined with RFA HCV-related primary HCC, Child–Pugh class A or B JPRN-UMIN000001701 2009 30 I/II Completed

  • Safe and well tolerated

  • Longer median RFS time for patients with OK432-stimulated DC vaccination than patients with non-OK432-stimulated DC vaccination (24.8 months versus 13.0 months)

 Kitahara et al. [40]
Mature-DC vaccine combined with TAE Primary HCC, Child–Pugh class A or B JPRN-UMIN000012702 2013 3 NA Completed NA NA
Mature-DC vaccine combined with TAE and RFA Unresectable primary HCC, Child–Pugh class A or B JPRN-UMIN000036065 2019 3 I Completed NA NA
Mature-DC vaccine combined with TAE and RFA Unresectable primary HCC, Child–Pugh class A or B JPRN-jRCTc050200107 2021 30 I/II Ongoing NA NA
Mature-DC vaccine (ilixadencel) co-activated with TLR3 and 7/8 agonists and IFN-γ and given in combination with molecular-targeted drug sorafenib Advanced primary HCC, BCLC stage B or C, Child–Pugh class A NCT01974661 2013 17 I Completed

  • Safe and well tolerated

  • 5.9% of patients with PR and 29.4% with SD; median TTP and OS times of 5.5 months and 7.5 months, respectively

  • 73.3% of evaluable patients with increased frequency of IFN-γ-producing CTLs in peripheral blood

 Rizell et al. [41]
Autologous-irradiated-HCC-tumor-stem-cell-pulsed mature-DC vaccine combined with surgical resection and TACE Unresectable HBV-related primary HCC, BCLC stage A or C, Child–Pugh class A NA 2013 8 I Completed

  • Safe and well tolerated

  • No increase in serum levels of hepatic transaminases, hepatitis B antigens, and viral DNA

 Wang et al. [42]
HepG2-HCC-cell-lysate-pulsed mature-DC vaccine combined with TACE Primary HCC, Child–Pugh class A or B ISRCTN11889464 2014 48 II Completed NA NA
HepG2-HCC-cell-lysate-pulsed mature-DC vaccine combined with TACE HCV-related primary HCC, BCLC stage B or D, Child–Pugh class A or B or C DRKS00016606 2015 20 II Completed

  • Safe and well tolerated

  • 60% with PR and 20% with SD in BCLC stage B patients with combined therapy similar to patients with TACE alone; 20% with PR and 40% with SD in BCLC stage D patients with vaccination compared to none with PR or SD in patients with supportive treatment

  • Increased frequency of peripheral CTLs and decreased serum levels of AFP

 Abdel Ghafar et al. [43]
Mature-DC vaccine co-pulsed with HBV-specific antigen peptides and HepG2 HCC cell lysate and given in combination with TACE Unresectable HBV-related primary HCC, BCLC stage B or C, Child–Pugh class A or B NCT03086564 2017 70 I/II Completed NA NA
Peptides-pulsed mature-DC vaccine combined with RFA Primary HCC, HLA-A24 positive JPRN-UMIN000020811 2016 10 NA Completed NA NA
Peptides-pulsed mature-DC vaccine combined with RFA Primary HCC, Child–Pugh class A or B JPRN-jRCTc040190093 2020 6 I Ongoing NA NA
HSP70-mRNA-transfected mature-DC vaccine combined with surgical resection Resectable primary HCC, LCSGJ (5th edition) stage II to IVA JPRN-UMIN000010691 2012 45 I/II Completed

  • Safe and well tolerated

  • Better median OS and DFS times for patients with HSP70-expressing HCC with combined therapy than patients with surgical resection alone

 Matsui et al. [44]
Mature-DC vaccine co-pulsed with AFP, MAGE-1, and GPC-3 proteins and given in combination with TACE Primary HCC, AJCC TNM (6th edition) stage II to IIIC, Child–Pugh class A or B NA 2009 5 I/II Completed

  • Safe and well tolerated

  • 20% of patients with SD

  • 100% of patients with increased IFN-γ-producing CTL responses against AFP, MAGE-1, and/or GPC-3 antigens

 Tada et al. [45]
Mature-DC vaccine co-pulsed with AFP, MAGE-1, and GPC-3 proteins and given in combination with TACE Unresectable primary HCC, Child–Pugh class A KCT0000986 2013 40 II Ongoing NA NA
Mature-DC vaccine co-pulsed with AFP, MAGE-1, and GPC-3 proteins and given in combination with surgical resection Primary HCC JPRN-UMIN000021545 2016 50 II Completed NA NA
Mature-DC vaccine co-pulsed with AFP, MAGE-1, and GPC-3 proteins and given in combination with surgical resection, RFA, PEI, or TACE Primary HCC, AJCC TNM (6th edition) stage I to IIIC, Child–Pugh class A or B KCT0000427 2009 12 I/IIa Completed

  • Safe and well tolerated

  • 75% of patients free of tumor recurrence up to 24 weeks and with stronger IFN-γ-producing CTL responses against AFP, MAGE-1, and/or GPC-3 antigens

  • Longer median TTP for patients with vaccination than patients without vaccination (36.6 months versus 11.8 moths)

 Lee et al. [46]
Mature-DC vaccine co-pulsed with AFP, MAGE-1, and GPC-3 proteins and given in combination with surgical resection, RFA, PEI, or TACE Primary HCC, AJCC TNM (6th edition) stage I to IIIC, Child–Pugh class A or B KCT0000008 2010 156 II Completed

  • Safe and well tolerated

  • 63% of patients with increased IFN-γ-producing CTL responses against AFP, MAGE-1, and/or GPC-3 antigens

  • Better RFS for non-RFA-treated patients with vaccination than patients without vaccination

 Lee et al. [47]
HCC-tumor-neoantigen-pulsed mature-DC vaccine combined with PMWA Primary HCC, HKLC stage IIa, Child–Pugh class A or B NCT03674073 2018 24 I Ongoing NA NA
HCC-tumor-neoantigen-pulsed mature-DC vaccine combined with ICI nivolumab and surgical resection Resectable primary or recurrent HCC, Child–Pugh class A NCT04912765 2021 60 II Ongoing NA NA
Multiple-HCC-tumor-antigens-pulsed mature-DC vaccine combined with surgical resection, TACE, or molecular-targeted drug sorafenib or lenvatinib HBV-related primary HCC, Child–Pugh class A or B NCT04317248 2020 600 II Ongoing NA NA
Combination of DC vaccines and immune effector cells and anticancer therapies
Autologous-HCC-tumor-lysate-pulsed mature-DC vaccine with CATs and combined with surgical resection Primary HCC NA 2000 94 II Completed

  • Safe and well tolerated

  • Longer median OS (97.7 months versus 41.0 months) and RFS (24.5 months versus 12.6 months) times for patients with combined therapy than patients with surgical resection alone

 Shimizu et al. [48]
Autologous-HCC-tumor-lysate-pulsed mature-DC vaccine with immature DCs, CIKs, mature-DC-precision CTLs, and mature DC-CIKs combined with PMWA HBV-related primary HCC, Child–Pugh class A or B NA NA 10 I Completed

  • Safe and well tolerated

  • 57.1% and 28.6% of evaluable patients with decreased and undetectable serum levels of viral DNA, respectively

 Zhou et al. [49]
Mature DC-CIKs combined with surgical resection or TACE Primary HCC NCT01821482 2013 100 II Ongoing NA NA
Mature-DC vaccine with CIKs and combined with molecular-targeted drug sorafenib Advanced primary HCC, BCLC stage B or C, Child–Pugh class A or B NA 2015 71 NA Completed

  • Safe and well tolerated

  • 11.4% with CR, 40% with PR, and 37.1% with SD in patients with combined therapy compared to 2.8% with CR, 13.9% with PR, and 25% with SD in patients with sorafenib alone; longer median OS time for patients with combined therapy than patients with sorafenib alone (18.6 months versus 13.8 moths)

  • Decreased serum levels of AFP

 Zhou et al. [50]
Mature-DC-precision multiple-antigen CTLs combined with surgical resection Primary HCC, Child–Pugh class A or B NCT02632188 2015 60 I/II Ongoing NA NA
Mature-DC-precision multiple-antigen CTLs combined with TACE Unresectable primary or recurrent HCC, Child–Pugh class A or B NCT02638857 2015 60 I/II Ongoing NA NA
Personalized HCC-tumor-neoantigen-pulsed mature-DC vaccine with mature-DC-precision neoantigen CTLs and combined with surgical resection or RFA Primary HCC, Child–Pugh class A or B NCT03067493 2017 10 II Completed

  • Safe and well tolerated

  • 50% of patients free of tumor recurrence for 2 years; 70% of patients with generation of de novo multiclonal neoantigen-specific CTL responses

  • Median DFS time of 18.3 months; better median DFS time for patients who generated immune responses than patients who did not generate immune responses

 Peng et al. [51]

Abbreviations: DC, dendritic cell; HCC, hepatocellular carcinoma; EBRT, external beam radiation therapy; NA, not available; PR, partial response; AFP, alpha-fetoprotein; AJCC, American Joint Committee on Cancer; TNM, tumor–node–metastasis; RFA, radiofrequency ablation; HCV, hepatitis C virus; TAE, transarterial embolization; TLR, Toll-like receptor; IFN-γ, interferon-gamma; BCLC, Barcelona Clinic Liver Cancer; SD, stable disease; TTP, time to progression; OS, overall survival; CTL, cytotoxic T lymphocyte; TACE, transarterial chemoembolization; HBV, hepatitis B virus; HLA, human leukocyte antigen; HSP70, heat-shock protein 70; LCSGJ, Liver Cancer Study Group of Japan; DFS, disease-free survival; MAGE-1, melanoma-associated antigen 1; GPC-3, glypican-3; PEI, percutaneous ethanol injection; PMWA, percutaneous microwave ablation; HKLC, Hong Kong Liver Cancer; ICI, immune checkpoint inhibitor; CAT, CD3-activated T cell; CIK, cytokine-induced killer cell; DC-CIK, dendritic-cell-activated cytokine-induced killer cell; CR, complete response.