Mouse alpha-fetoprotein-specific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice.
OBJECTIVE
alpha-Fetoprotein (AFP) is a tumor-associated protein that is frequently expressed at high levels in hepatocellular carcinoma (HCC). The aim of the study was to characterize self-reactive cytotoxic T lymphocytes (CTLs) directed against murine AFP (mAFP) after DNA-based immunization in mice.


METHODS
To study CTL responses, mAFP-expressing recombinant vaccinia viruses were generated. An HCC tumor model was established in C57L/J mice by injection of syngeneic endogenously mAFP-expressing Hepa1-6 cells.


RESULTS
Gene gun and intramuscular coimmunizations of DNA expression vectors encoding mAFP with plasmids encoding murine interleukin (IL)-12, granulocyte-macrophage colony-stimulating factor, or IL-18 induced weak CTL activity against mAFP in different mouse strains. Some mice developed anti-mAFP antibody responses, suggesting breaking of immunologic ignorance. No hepatocyte damage was detectable despite low-level endogenous hepatic mAFP expression. Therapeutic immunizations of mice bearing mAFP-expressing murine HCCs induced partial regression of tumors. A significant survival benefit was observed in mice immunized with mAFP expression vector DNA but not in untreated mice or in mice immunized with mock/cytokine plasmid DNA.


CONCLUSIONS
The data show that AFP may be used as a potential self tumor antigen to induce CTL and CD4(+) T cell-mediated regression of AFP-expressing HCC by DNA-based immunization.
Grimm
C F
CF
Department of Medicine II, University Hospital of Freiburg, Freiburg, Germany.
Ortmann
D
D
Mohr
L
L
Michalak
S
S
Krohne
T U
TU
Meckel
S
S
Eisele
S
S
Encke
J
J
Blum
H E
HE
Geissler
M
M
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001219:Aspartate Aminotransferases / Q000097:blood; D019470:Biolistics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000509:alpha-Fetoproteins / Q000032:analysis / Q000235:genetics*
D000911:Antibodies, Monoclonal; D020382:Interleukin-18; D000509:alpha-Fetoproteins; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase