Subscribe to RSS
DOI: 10.1055/s-2003-44304
Immunobiology and Gene-Based Immunotherapy of Hepatocellular Carcinoma
Immunbiologie und Immuntherapie des hepatozellulären KarzinomsPublication History
Manuscript received: 3. April 2003
Accepted after revision: 17. April 2003
Publication Date:
01 December 2003 (online)

Zusammenfassung
Einleitung: Das hepatozelluläre Karzinom (HCC) ist einer der häufigsten Tumoren weltweit mit ca. 1 Million Neuerkrankungen pro Jahr. Die Resektion und Lebertransplantation sind die bisher einzigen potenziell kurativen Therapieansätze in ausgewählten Fällen. Lokalablative Verfahren sind komplikationsarm, aber häufig mit Lokalrezidiven, intrahepatischen Metastasen oder neuen HCC-Herden in der zirrhotischen Leber assoziiert. Deshalb sind neue therapeutische Ansätze gegen das HCC und ein verbessertes Verständnis der HCC-Immunbiologie von hoher Priorität. In diesem Artikel sollen neue molekulare Therapieansätze zur Behandlung des HCC und die dafür notwendigen immunpathogenetischen Zusammenhänge dargestellt werden. Material und Methoden: Eine systematische Medline-Literatursuche wurde in allen zitierten Sprachen ab 1970 durchgeführt. Ergebnisse: Eine Vielzahl spezifischer und unspezifischer immunstimulierender Strategien gegen das HCC wurde bisher in präklinischen experimentellen Modellen mit viel versprechenden Resultaten untersucht. Obwohl die bisherigen tumorimmuntherapeutischen Ansätze nur mäßigen klinischen Erfolg bei verschiedenen Tumorentitäten zeigten, konnten mittels neuer molekularer Methoden in den letzten Jahren neue Tumorantigene wie das α-Fetoprotein (AFP) identifiziert werden. Das verbesserte Verständnis der Tumorimmunbiologie ist der Grundstein für eine erfolgreiche Immuntherapie von Tumoren. Erste klinische Phase-I- und -II-Studien mit dem Ziel einer HCC-Immuntherapie unter Verwendung dendritischer Zellen als zelluläres Adjuvans zur Tumorantigenvakzinierung sind inzwischen initiiert. Eine Korrelation von klinischem Verlauf und Monitoring der Immuneffektoren nach Tumorvakzinierung kann mittels neuer immunologischer Techniken, die Immuneffektoren auf Einzelzellebene charakterisieren und in vivo verfolgen können, durchgeführt werden. Zukünftige immuntherapeutische klinische Studien lassen prognostische Parameter für bestimmte Patientenuntergruppen, optimierte Vakzinierungsprotokolle und neue immunologisch-molekulare Surrogatmarker für die Diagnostik von HCCs erwarten.
Abstract
Purpose: Hepatocellular carcinoma (HCC) is one of the major malignancies worldwide. For most patients with advanced or multifocal HCC treatment options are limited resulting in a poor prognosis. Several local ablation methods have been developed as minimally invasive strategies for HCC treatment. It is unclear, until now, whether these therapies will significantly improve the poor prognosis of patients with unresectable HCC. Novel therapeutic strategies and a better understanding of HCC imunobiology are, therefore, urgently required.
Design: The scientific literature since 1970 in all languages cited in Medline was systematically reviewed. Results: Until now, a variety of specific and non-specific immunostimulatory strategies against HCC has been applied in preclinical experimental models with some promising results. The molecular characterization of HCC associated tumour antigens such as α-fetoprotein (AFP) and the increased understanding of the immunological pathways involved in liver and tumor immunology have paved the way for the design of promising gene-based cancer vaccines. The first phase I and II immunotherapeutic clinical trials based on dendritic cell immunotherapy and peptide vaccines are ongoing in HCC-patients. Clinical trials have, in general, demonstrated the safety of such strategies. Recently, exciting new immunological techniques and tools have been developed which allow to characterize antigen specific T cells at a single-cell level. In future, HCC specific tumor rejection antigens which can be used therapeutically have to be identified using microarray-based analysis. The different therapeutic modalities need to be compared directly resulting in optimised therapeutic approaches and the identification of sub-groups of HCC-patients responding favourably to treatment.
Schlüsselwörter
HCC - Immuntherapie - Gentherapie - Zytokine - dendritische Zellen - T-Zelle
Key words
HCC - immunotherapy - gene therapy - dendritic cells - T cell - cytokines
References
- 1
Bosch F X, Ribes J, Borras J.
Epidemiology of primary liver cancer.
Sem Liv Dis.
1999;
19
271-285
MissingFormLabel
- 2
De Vos I, Goldberg D, Hole D J. et al .
Trends in primary liver cancer.
Lancet.
1998;
351
215-216
MissingFormLabel
- 3
El-Serag H B, Mason A C.
Rising incidence of hepatocellular carcinoma in the United States.
N Engl J Med.
1999;
340
745-750
MissingFormLabel
- 4
Okuda K.
Early recognition of hepatocellular carcinoma.
Hepatology.
1986;
6
729-738
MissingFormLabel
- 5
Bismuth H, Chiche L, Adam R. et al .
Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients.
Ann Surg.
1993;
218
145-151
MissingFormLabel
- 6
Allgaier H P, Galandi D, Zuber I. et al .
Radiofrequency thermal ablation of hepatocellular carcinoma.
Dig Dis.
2001;
19
301-310
MissingFormLabel
- 7
Mohr L, Geissler M, Blum H E.
Gene therapy for malignant liver disease.
Expert Opin Biol Ther.
2002;
2
163-175
MissingFormLabel
- 8
Geissler M, Mohr L, Blum H E.
Immunotherapy of hepatocellular carcinoma.
Dtsch Med Wochenschr.
2001;
126
1464-1466
MissingFormLabel
- 9
Butterfield L H, Ribas A.
Immunotherapy of hepatocellular carcinoma.
Expert Opin Biol Ther.
2002;
2
123-133
MissingFormLabel
- 10
Yee C, Riddell S R, Greenberg P D.
Prospects for adoptive T cell therapy.
Curr Opin Immunol.
1997;
9
702-708
MissingFormLabel
- 11
Renner C, Kubuschok B, Trumper L. et al .
Clinical approaches to vaccination in oncology.
Ann Hematol.
2001;
80
255-266
MissingFormLabel
- 12
Wild C P, Hall A J.
Primary prevention of hepatocellular carcinoma in developing countries.
Mutat Res.
2000;
462
381-393
MissingFormLabel
- 13
Schultze J L, Maecker B, von Bergwelt-Baildon M S. et al .
Tumour immunotherapy: new tools, new treatment modalities and new T-cell antigens.
Vox Sang.
2001;
80
81-89
MissingFormLabel
- 14
Mumberg D, Wick M, Schreiber H.
Unique tumor antigens redefined as mutant tumor-specific antigens.
Semin Immunol.
1996;
8
289-293
MissingFormLabel
- 15
Kurokohchi K, Carrington M, Mann D L. et al .
Expression of HLA class I molecules and the transporter associated with antigen processing
in hepatocellular carcinoma.
Hepatology.
1996;
23
1181-1188
MissingFormLabel
- 16
Ricci G, Colombo C, Ghiazza B. et al .
HLA-A, B, C, DR and DQ expression and hepatocellular carcinoma: study of 205 Italian
subjects.
Cancer Lett.
1995;
98
121-125
MissingFormLabel
- 17
Paterson A C, Sciot R, Kew M C. et al .
HLA expression in human hepatocellular carcinoma.
Br J Cancer.
1988;
57
369-373
MissingFormLabel
- 18
Nagao M, Nakajima Y, Kanehiro H. et al .
The impact of interferon gamma receptor expression on the mechanism of escape from
host immune surveillance in hepatocellular carcinoma.
Hepatology.
2000;
32
491-500
MissingFormLabel
- 19
Kanzler S, Meyer E, Lohse A W. et al .
Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor
accelerates chemically induced hepatocarcinogenesis.
Oncogene.
2001;
20
5015-5024
MissingFormLabel
- 20
Bissell D M, Roulot D, George J.
Transforming growth factor beta and the liver.
Hepatology.
2001;
34
859-867
MissingFormLabel
- 21
Gorelik L, Fields P E, Flavell R A.
Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3
expression.
J Immunol.
2000;
165
4773-4777
MissingFormLabel
- 22
Gorelik L, Flavell R A.
Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation
and autoimmune disease.
Immunity.
2000;
12
171-181
MissingFormLabel
- 23
Kim K Y, Jeong S Y, Won J. et al .
Induction of angiogenesis by expression of soluble type II transforming growth factor-beta
receptor in mouse hepatoma.
J Biol Chem.
2001;
276
38781-38786
MissingFormLabel
- 24
Maggard M, Meng L, Ke B. et al .
Antisense TGF-beta2 immunotherapy for hepatocellular carcinoma: treatment in a rat
tumor model.
Ann Surg Oncol.
2001;
8
32-37
MissingFormLabel
- 25
Gorelik L, Flavell R A.
Immune-mediated eradication of tumors through the blockade of transforming growth
factor-beta signaling in T cells.
Nat Med.
2001;
7
1118-1122
MissingFormLabel
- 26
Nagao M, Nakajima Y, Hisanaga M. et al .
The alteration of Fas receptor and ligand system in hepatocellular carcinomas: how
do hepatoma cells escape from the host immune surveillance in vivo?.
Hepatology.
1999;
30
413-421
MissingFormLabel
- 27
Patel T.
Immune escape in hepatocellular cancer: is a good offense the best defense?.
Hepatology.
1999;
30
576-578
MissingFormLabel
- 28
Strand S, Hofmann W J, Hug H. et al .
Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells - a
mechanism of immune evasion?.
Nat Med.
1996;
2
1361-1366
MissingFormLabel
- 29
Galle P R, Hofmann W J, Walczak H. et al .
Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage.
J Exp Med.
1995;
182
1223-1230
MissingFormLabel
- 30
Weidmann E, Whiteside T L, Giorda R. et al .
The T-cell receptor V beta gene usage in tumor-infiltrating lymphocytes and blood
of patients with hepatocellular carcinoma.
Cancer Res.
1992;
52
5913-5920
MissingFormLabel
- 31
Takagi S, Chen K, Schwarz R. et al .
Functional and phenotypic analysis of tumor-infiltrating lymphocytes isolated from
human primary and metastatic liver tumors and cultured in recombinant interleukin-2.
Cancer.
1989;
63
102-111
MissingFormLabel
- 32
Wada Y, Nakashima O, Kutami R. et al .
Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration.
Hepatology.
1998;
27
407-414
MissingFormLabel
- 33
Zhang L, Conejo-Garcia J R, Katsaros D. et al .
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
N Engl J Med.
2003;
348
203-213
MissingFormLabel
- 34
Shields P L, Morland C M, Salmon M. et al .
Chemokine and chemokine receptor interactions provide a mechanism for selective T
cell recruitment to specific liver compartments within hepatitis C-infected liver.
J Immunol.
1999;
163
6236-6243
MissingFormLabel
- 35
Yoong K F, McNab G, Hubscher S G. et al .
Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor-infiltrating
lymphocytes to tumor endothelium in human hepatocellular carcinoma.
J Immunol.
1998;
160
3978-3988
MissingFormLabel
- 36
Yoong K F, Afford S C, Jones R. et al .
Expression and function of CXC and CC chemokines in human malignant liver tumors:
a role for human monokine induced by gamma-interferon in lymphocyte recruitment to
hepatocellular carcinoma.
Hepatology.
1999;
30
100-111
MissingFormLabel
- 37
Pockaj B A, Sherry R M, Wei J P. et al .
Localization of 111indium-labeled tumor infiltrating lymphocytes to tumor in patients
receiving adoptive immunotherapy. Augmentation with cyclophosphamide and correlation
with response.
Cancer.
1994;
73
1731-1737
MissingFormLabel
- 38
Yoneyama H, Matsuno K, Zhang Y. et al .
Regulation by chemokines of circulating dendritic cell precursors, and the formation
of portal tract-associated lymphoid tissue, in a granulomatous liver disease.
J Exp Med.
2001;
193
35-49
MissingFormLabel
- 39
Chen S, Akbar S M, Tanimoto K. et al .
Absence of CD83-positive mature and activated dendritic cells at cancer nodules from
patients with hepatocellular carcinoma: relevance to hepatocarcinogenesis.
Cancer Lett.
2000;
148
49-57
MissingFormLabel
- 40
Ninomiya T, Akbar S M, Masumoto T. et al .
Dendritic cells with immature phenotype and defective function in the peripheral blood
from patients with hepatocellular carcinoma.
J Hepatol.
1999;
31
323-331
MissingFormLabel
- 41
Kakumu S, Ito S, Ishikawa T. et al .
Decreased function of peripheral blood dendritic cells in patients with hepatocellular
carcinoma with hepatitis B and C virus infection.
J Gastroenterol Hepatol.
2000;
15
431-436
MissingFormLabel
- 42
Knolle P A, Limmer A.
Neighborhood politics: the immunoregulatory function of organ-resident liver endothelial
cells.
Trends Immunol.
2001;
22
432-437
MissingFormLabel
- 43
Abe M, Akbar S M, Horiike N. et al .
Induction of cytokine production and proliferation of memory lymphocytes by murine
liver dendritic cell progenitors: role of these progenitors as immunogenic resident
antigen-presenting cells in the liver.
J Hepatol.
2001;
34
61-67
MissingFormLabel
- 44
Chuma M, Sakamoto M, Yamazaki K. et al .
Expression profiling in multistage hepatocarcinogenesis: identification of HSP70 as
a molecular marker of early hepatocellular carcinoma.
Hepatology.
2003;
37
198-207
MissingFormLabel
- 45
Chung E J, Sung Y K, Farooq M. et al .
Gene expression profile analysis in human hepatocellular carcinoma by cDNA microarray.
Mol Cells.
2002;
14
382-387
MissingFormLabel
- 46
Dominguez-Malagon H, Gaytan-Graham S.
Hepatocellular carcinoma: an update.
Ultrastruct Pathol.
2001;
25
497-516
MissingFormLabel
- 47
Delpuech O, Trabut J B, Carnot F. et al .
Identification, using cDNA macroarray analysis, of distinct gene expression profiles
associated with pathological and virological features of hepatocellular carcinoma.
Oncogene.
2002;
21
2926-2937
MissingFormLabel
- 48
Li Y, Tang R, Xu H. et al .
Discovery and analysis of hepatocellular carcinoma genes using cDNA microarrays.
J Cancer Res Clin Oncol.
2002;
128
369-379
MissingFormLabel
- 49
Xu X R, Huang J, Xu Z G. et al .
Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene
expression profiles of hepatocellular carcinoma with those of corresponding noncancerous
liver.
Proc Natl Acad Sci U S A.
2001;
98
15089-15094
MissingFormLabel
- 50
Yamashita T, Hashimoto S, Kaneko S. et al .
Comprehensive gene expression profile of a normal human liver.
Biochem Biophys Res Commun.
2000;
269
110-116
MissingFormLabel
- 51
Guo J, Cai M, Wei D. et al .
Immune responses of dendritic cells after loaded with cytotoxicity T lymphocyte epitope
based peptide of human alpha-fetoprotein (hAFP).
Zhonghua Gan Zang Bing Za Zhi.
2002;
10
178-180
MissingFormLabel
- 52
Hanke P, Rabe C, Serwe M. et al .
Cirrhotic patients with or without hepatocellular carcinoma harbour AFP-specific T-lymphocytes
that can be activated in vitro by human alpha-fetoprotein.
Scand J Gastroenterol.
2002;
37
949-955
MissingFormLabel
- 53
Geissler M, Mohr L, Köhler G. et al .
Immunotherapy Directed Against alpha-Fetoprotein Results in Autoimmune Liver Disease
During Liver Regeneration in Mice.
Gastroenterology.
2001;
121
931-939
MissingFormLabel
- 54
Butterfield L H, Koh A, Meng W. et al .
Generation of human T-cell responses to an HLA-A2.1-restricted peptide epitope derived
from alpha-fetoprotein.
Cancer Res.
1999;
59
3134-3142
MissingFormLabel
- 55
Butterfield L H, Meng W S, Koh A. et al .
T cell responses to HLA-A*0201-restricted peptides derived from human alpha fetoprotein.
J Immunol.
2001;
166
5300-5308
MissingFormLabel
- 56
Meng W S, Butterfield L H, Ribas A. et al .
Fine specificity analysis of an HLA-A2.1-restricted immunodominant T cell epitope
derived from human alpha-fetoprotein.
Mol Immunol.
2000;
37
943-950
MissingFormLabel
- 57
Meng W S, Butterfield L H, Ribas A. et al .
alpha-Fetoprotein-specific tumor immunity induced by plasmid prime-adenovirus boost
genetic vaccination.
Cancer Res.
2001;
61
8782-8786
MissingFormLabel
- 58
Lee W C, Wang H C, Jeng L B. et al .
Effective treatment of small murine hepatocellular carcinoma by dendritic cells.
Hepatology.
2001;
34
896-905
MissingFormLabel
- 59
Homma S, Toda G, Gong J. et al .
Preventive antitumor activity against hepatocellular carcinoma (HCC) induced by immunization
with fusions of dendritic cells and HCC cells in mice.
J Gastroenterol.
2001;
36
764-771
MissingFormLabel
- 60
Vollmer C M Jr, Eilber F C, Butterfield L H. et al .
Alpha-fetoprotein-specific genetic immunotherapy for hepatocellular carcinoma.
Cancer Res.
1999;
59
3064-3067
MissingFormLabel
- 61
Ladhams A, Schmidt C, Sing G. et al .
Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed
dendritic cells.
J Gastroenterol Hepatol.
2002;
17
889-896
MissingFormLabel
- 62
Chan R C, Xie H, Zhao G P. et al .
Dendritomas formed by fusion of mature dendritic cells with allogenic human hepatocellular
carcinoma cells activate autologous cytotoxic T lymphocytes.
Immunol Lett.
2002;
83
101-109
MissingFormLabel
- 63
Grimm C F, Ortmann D, Mohr L. et al .
Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma
leads to tumor regression in mice.
Gastroenterology.
2000;
119
1104-1112
MissingFormLabel
- 64
Schlott T, Ahrens K, Ruschenburg I. et al .
Different gene expression of MDM2, GAGE-1, -2 and FHIT in hepatocellular carcinoma
and focal nodular hyperplasia.
Br J Cancer.
1999;
80
73-78
MissingFormLabel
- 65
Kobayashi Y, Higashi T, Nouso K. et al .
Expression of MAGE, GAGE and BAGE genes in human liver diseases: utility as molecular
markers for hepatocellular carcinoma.
J Hepatol.
2000;
32
612-617
MissingFormLabel
- 66
Chen Y T, Scanlan M J, Sahin U. et al .
A testicular antigen aberrantly expressed in human cancers detected by autologous
antibody screening.
Proc Natl Acad Sci U S A.
1997;
94
1914-1918
MissingFormLabel
- 67
Mohr L, Schauer J I, Boutin R H. et al .
Targeted gene transfer to hepatocellular carcinoma cells in vitro using a novel monoclonal
antibody-based gene delivery system.
Hepatology.
1999;
29
82-89
MissingFormLabel
- 68
Moradpour D, Compagnon B, Wilson B E. et al .
Specific targeting of human hepatocellular carcinoma cells by immunoliposomes in vitro.
Hepatology.
1995;
22
1527-1537
MissingFormLabel
- 69
Tanaka S, Wands J R.
Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells
prevents transforming growth factor beta1-induced apoptosis.
Cancer Res.
1996;
56
3391-3394
MissingFormLabel
- 70
Nishiyama M, Wands J R.
Cloning and increased expression of an insulin receptor substrate-1-like gene in human
hepatocellular carcinoma.
Biochem Biophys Res Commun.
1992;
183
280-285
MissingFormLabel
- 71
Ince N, de la Monte S M, Wands J R.
Overexpression of human aspartyl (asparaginyl) beta-hydroxylase is associated with
malignant transformation.
Cancer Res.
2000;
60
1261-1266
MissingFormLabel
- 72
Lavaissiere L, Jia S, Nishiyama M. et al .
Overexpression of human aspartyl(asparaginyl)beta-hydroxylase in hepatocellular carcinoma
and cholangiocarcinoma.
J Clin Invest.
1996;
98
1313-1323
MissingFormLabel
- 73
Bergsland E K.
Molecular mechanisms underlying the development of hepatocellular carcinoma.
Semin Oncol.
2001;
28
521-531
MissingFormLabel
- 74
Covini G, Chan E K, Nishioka M. et al .
Immune response to cyclin B1 in hepatocellular carcinoma.
Hepatology.
1997;
25
75-80
MissingFormLabel
- 75
Yutani S, Shichijo S, Inoue Y. et al .
Expression of the SART1 tumor-rejection antigen in hepatocellular carcinomas.
Oncol Rep.
2001;
8
369-372
MissingFormLabel
- 76
Noguchi K, Enjoji M, Nakamuta M. et al .
Expression of a tumor-associated antigen RCAS1 in hepatocellular carcinoma.
Cancer Lett.
2001;
168
197-202
MissingFormLabel
- 77
Nakashima M, Sonoda K, Watanabe T.
Inhibition of cell growth and induction of apoptotic cell death by the human tumor-associated
antigen RCAS1.
Nat Med.
1999;
5
938-942
MissingFormLabel
- 78
Wang Y, Han K J, Pang X W. et al .
Large scale identification of human hepatocellular carcinoma-associated antigens by
autoantibodies.
J Immunol.
2002;
169
1102-1109
MissingFormLabel
- 79
Chun E, Lee J, Cheong H S. et al .
Tumor eradication by hepatitis B virus × antigen-specific CD8(+) T cells in xenografted
nude mice.
J Immunol.
2003;
170
1183-1190
MissingFormLabel
- 80
Steerenberg P A, Geerse E, De Jong W H. et al .
Tumour rejection after adoptive transfer of line-10-immune spleen cells is mediated
by two T cell subpopulations.
Cancer Immunol Immunother.
1991;
34
103-110
MissingFormLabel
- 81
Takayama T, Makuuchi M, Sekine T. et al .
Distribution and therapeutic effect of intraarterially transferred tumor-infiltrating
lymphocytes in hepatic malignancies. A preliminary report.
Cancer.
1991;
68
2391-2396
MissingFormLabel
- 82
Aruga A, Yamauchi K, Takasaki K. et al .
Induction of autologous tumor-specific cytotoxic T cells in patients with liver cancer.
Characterizations and clinical utilization.
Int J Cancer.
1991;
49
19-24
MissingFormLabel
- 83
Onishi S, Saibara T, Fujikawa M. et al .
Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin
2 in patients with unresectable hepatocellular carcinoma.
Hepatology.
1989;
10
349-353
MissingFormLabel
- 84
Kanai T, Monden M, Takeda T. et al .
Adoptive immunotherapy in patients with multiple hepatic cancers using lymphokine
activated killer cells (LAK) and interleukin-2.
Gan To Kagaku Ryoho.
1993;
20
1457-1460
MissingFormLabel
- 85
Wang Y, Chen H, Wu M. et al .
Postoperative immunotherapy for patients with hepatocarcinoma using tumor-infiltrating
lymphocytes.
Chin Med J (Engl).
1997;
110
114-117
MissingFormLabel
- 86
Takayama T, Sekine T, Makuuchi M. et al .
Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma:
a randomised trial.
Lancet.
2000;
356
802-807
MissingFormLabel
- 87
Friedl J, Stift A, Paolini P. et al .
Tumor antigen pulsed dendritic cells enhance the cytolytic activity of tumor infiltrating
lymphocytes in human hepatocellular cancer.
Cancer Biother Radiopharm.
2000;
15
477-486
MissingFormLabel
- 88
Ilan Y, Gabay E, Amit G. et al .
Suppression of human hepatoma in mice through adoptive transfer of immunity to the
hepatitis B surface antigen.
J Hepatol.
1997;
27
170-175
MissingFormLabel
- 89
Romieu R, Baratin M, Kayibanda M. et al .
Passive but not active CD8+ T cell-based immunotherapy interferes with liver tumor
progression in a transgenic mouse model.
J Immunol.
1998;
161
5133-5137
MissingFormLabel
- 90
Siegel J P, Puri R K.
Interleukin-2 toxicity.
J Clin Oncol.
1991;
9
694-704
MissingFormLabel
- 91
Suto T, Fukuda S, Moriya N. et al .
Clinical study of biological response modifiers as maintenance therapy for hepatocellular
carcinoma.
Cancer Chemother Pharmacol.
1994;
33 Suppl
S145-S148
MissingFormLabel
- 92
Ichida T, Higuchi K, Arakawa K. et al .
Treatment of hepatocellular carcinoma utilizing lymphokine-activated killer cells
and interleukin-2.
Cancer Chemother Pharmacol.
1989;
23 Suppl
S45-S48
MissingFormLabel
- 93
Uchino J, Une Y, Kawata A. et al .
Postoperative chemoimmunotherapy for the treatment of liver cancer.
Semin Surg Oncol.
1993;
9
332-336
MissingFormLabel
- 94
Sangro B, Qian C, Schmitz V. et al .
Gene therapy of hepatocellular carcinoma and gastrointestinal tumors.
Ann N Y Acad Sci.
2002;
963
6-12
MissingFormLabel
- 95
He P, Tang Z Y, Ye S L. et al .
The targeted expression of interleukin-2 in human hepatocellular carcinoma cells.
J Exp Clin Cancer Res.
2000;
19
183-187
MissingFormLabel
- 96
Huang H, Chen S H, Kosai K. et al .
Gene therapy for hepatocellular carcinoma: long-term remission of primary and metastatic
tumors in mice by interleukin-2 gene therapy in vivo.
Gene Ther.
1996;
3
980-987
MissingFormLabel
- 97
Atarashi Y, Yasumura S, Nambu S. et al .
A novel human tumor necrosis factor alfa mutein, F4614, inhibits in vitro and in vivo
growth of murine and human hepatoma: implication for immunotherapy of human hepatocellular
carcinoma.
Hepatology.
1998;
28
57-67
MissingFormLabel
- 98
Cao G, Kuriyama S, Du P. et al .
Complete regression of established murine hepatocellular carcinoma by in vivo tumor
necrosis factor alpha gene transfer.
Gastroenterology.
1997;
112
501-510
MissingFormLabel
- 99
Schmitz V, Barajas M, Wang L. et al .
Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular
carcinoma.
Hepatology.
2001;
34
72-81
MissingFormLabel
- 100
Li Z, Sui Y, Jiang Y. et al .
Reconstruction of SEA-B7.1 double signals on human hepatocellular carcinoma cells
and analysis of its immunological effect.
Biochem Biophys Res Commun.
2001;
288
454-461
MissingFormLabel
- 101
Yamashita Y I, Shimada M, Hasegawa H. et al .
Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma
in the mice model.
Cancer Res.
2001;
61
1005-1012
MissingFormLabel
- 102
Barajas M, Mazzolini G, Genove G. et al .
Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding
for interleukin 12.
Hepatology.
2001;
33
52-61
MissingFormLabel
- 103
Putzer B M, Stiewe T, Rodicker F. et al .
Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated
delivery of interleukin 12/B7.1 genes.
J Natl Cancer Inst.
2001;
93
472-479
MissingFormLabel
- 104
Tatsumi T, Takehara T, Kanto T. et al .
B7 - 1 (CD80)-gene transfer combined with interleukin-12 administration elicits protective
and therapeutic immunity against mouse hepatocellular carcinoma.
Hepatology.
1999;
30
422-429
MissingFormLabel
- 105
Wang Z, Qiu S J, Ye S L. et al .
Combined IL-12 and GM-CSF gene therapy for murine hepatocellular carcinoma.
Cancer Gene Ther.
2001;
8
751-758
MissingFormLabel
- 106
Andrews K J, Ribas A, Butterfield L H. et al .
Adenovirus-interleukin-12-mediated tumor regression in a murine hepatocellular carcinoma
model is not dependent on CD1-restricted natural killer T cells.
Cancer Res.
2000;
60
6457-6464
MissingFormLabel
- 107
Kroger A, Ortmann D, Krohne T U. et al .
Growth suppression of the hepatocellular carcinoma cell line Hepa1 - 6 by an activatable
interferon regulatory factor-1 in mice.
Cancer Res.
2001;
61
2609-2617
MissingFormLabel
- 108
Narvaiza I, Mazzolini G, Barajas M. et al .
Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible
protein-10 and another encoding IL-12, results in marked antitumoral synergy.
J Immunol.
2000;
164
3112-3122
MissingFormLabel
- 109
Martinet O, Ermekova V, Qiao J Q. et al .
Immunomodulatory gene therapy with interleukin 12 and 4 - 1BB ligand: long-term remission
of liver metastases in a mouse model.
J Natl Cancer Inst.
2000;
92
931-936
MissingFormLabel
- 110
Geutskens S B, van der Eb M M, Plomp A C. et al .
Recombinant adenoviral vectors have adjuvant activity and stimulate T cell responses
against tumor cells.
Gene Ther.
2000;
7
1410-1416
MissingFormLabel
- 111
Bramson J L, Bodner C A, Graham R W.
Activation of host antitumoral responses by cationic lipid/DNA complexes.
Cancer Gene Ther.
2000;
7
353-359
MissingFormLabel
- 112
Tatsumi T, Takehara T, Kanto T. et al .
Administration of interleukin-12 enhances the therapeutic efficacy of dendritic cell-based
tumor vaccines in mouse hepatocellular carcinoma.
Cancer Res.
2001;
61
7563-7567
MissingFormLabel
- 113
Cao X, Wang J, Zhang W. et al .
Treatment of human hepatocellular carcinoma by fibroblast-mediated human interferon
alpha gene therapy in combination with adoptive chemoimmunotherapy.
J Cancer Res Clin Oncol.
1995;
121
457-462
MissingFormLabel
- 114
Salvadori S, Martinelli G, Zier K.
Resection of solid tumors reverses T cell defects and restores protective immunity.
J Immunol.
2000;
164
2214-2220
MissingFormLabel
- 115
Schueller G, Paolini P, Friedl J. et al .
Heat treatment of hepatocellular carcinoma cells: increased levels of heat shock proteins
70 and 90 correlate with cellular necrosis.
Anticancer Res.
2001;
21
295-300
MissingFormLabel
- 116
Gallucci S, Lolkema M, Matzinger P.
Natural adjuvants: endogenous activators of dendritic cells.
Nat Med.
1999;
5
1249-1255
MissingFormLabel
- 117
Shi Y, Zheng W, Rock K L.
Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses.
Proc Natl Acad Sci U S A.
2000;
97
14590-14595
MissingFormLabel
- 118
Geissler M, Ali M, Ritter M. et al .
Local ablation of hepatocellular carcinoma results in activation of dendritic cells
and tumor specific T cell responses.
Hepatology.
2002;
36
696A
MissingFormLabel
- 119
Boon T, Cerottini J C, van den Eynde B. et al .
Tumor antigens recognized by T lymphocytes.
Annu Rev Immunol.
1994;
12
337-365
MissingFormLabel
- 120
Schultze J L, Vonderheide R H.
From cancer genomics to cancer immunotherapy: toward second-generation tumor antigens.
Trends Immunol.
2001;
22
516-523
MissingFormLabel
- 121
Vonderheide R H, Schultze J L, Anderson K S. et al .
Equivalent induction of telomerase-specific cytotoxic T lymphocytes from tumor-bearing
patients and healthy individuals.
Cancer Res.
2001;
61
8366-8370
MissingFormLabel
Michael Geissler, M.D.
Department of Medicine II, University Hospital Freiburg
Hugstetter Straße 55
79106 Freiburg
Email: mgeissl@ukl.uni-freiburg.de