Antisense TGF-beta2 immunotherapy for hepatocellular carcinoma: treatment in a rat tumor model.
BACKGROUND
The overexpression of transforming growth factor-beta (TGF-beta) in hepatocellular carcinoma (HCC) appears to induce immunosuppression toward the tumor cells.


METHODS
A rat HCC cell line, Morris hepatoma rat cell line (MRH)-7777 (MRH), was transfected with antisense TGF-beta2 in pCEP-4 vector and used as immunotherapy against the development of wild-type tumors. An enzyme-linked immunosorbent assay (ELISA) confirmed that TGF-beta2 production was markedly lower for antisense modified cells as compared to wild-type tumor cells. Tumors were initiated by injecting MRH cells into the flanks of Buffalo rats. This was followed by biweekly vaccinations with irradiated MRH cells (unmodified, pCEP-4 alone, or antisense TGF-beta2 modified).


RESULTS
In the group that received irradiated MRH unmodified cells, 55% of rats died from tumor burden, and 36% developed tumor regression. In the group that received irradiated MRH cells modified with pCEP-4 vector alone, 50% died from tumors and 33% had spontaneous regression. In animals treated with pCEP-4/TGF-beta antisense modified cells, none developed tumors. Cell-mediated cytotoxicity assays demonstrated a twofold increase in lytic activity in the effector cells of the animals treated with antisense modified cells.


CONCLUSIONS
These results demonstrate the successful treatment of HCC tumors in rats by a HCC vaccine genetically altered with antisense TGF-beta2. Decreased production of TGF-beta in HCC vaccine enhances immunogenicity against wild-type HCC tumor cells.
Maggard
M
M
Department of Surgery, UCLA Medical Center, UCLA School of Medicine, Los Angeles, California, USA.
Meng
L
L
Ke
B
B
Allen
R
R
Devgan
L
L
Imagawa
D K
DK
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D016373:DNA, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007279:Injections, Subcutaneous; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000139:chemically induced; D010957:Plasmids; D051381:Rats; D011915:Rats, Inbred BUF; D012190:Retroviridae; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics*; D053781:Transforming Growth Factor beta2; D014407:Tumor Cells, Cultured; D014611:Vaccination
D016373:DNA, Antisense; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2