Does preventive vaccination with engineered tumor cells work in cancer-prone transgenic mice?
The use of genetically modified tumor cells as vaccines has been successful in numerous animal models of grafted syngenic tumors and has provided the groundwork for many clinical trials of gene therapy in cancer patients. To investigate the real efficacy of ex vivo gene therapy-based vaccines, we used transgenic mice that express the SV40 large T and small t antigens under the control of hepatic antithrombin III (ASV-B)-regulatory sequences. These mice systematically develop hepatocarcinoma. Hepatoma cells, derived from ASV-B transgenic mice, were gene-transduced to express either interleukin-2, interleukin-4, the granulocyte-macrophage colony-stimulating factor, or the T-cell costimulatory molecule B7.1. First, we demonstrated the vaccine potential of engineered hepatoma cells by immunizing nontransgenic mice with these cells, which prevented the growth of subsequent grafted nontransduced hepatoma cells. However, vaccination of pretumoral transgenic animals with various combinations of engineered hepatoma cells failed to inhibit hepatoma onset and progression. Rather, tumor development in ASV-B mice appears to be dependent on the immune system, since neonatal induction of immunotolerance to tumor in ASV-B mice cells was associated with a moderate, but significant, acceleration of tumor development. These results seriously call into question the efficacy of this strategy of active vaccinotherapy against natural tumors.
Morel
A
A
U129 INSERM, Institut Cochin de Génétique Moléculaire, Paris, France.
de La Coste
A
A
Fernandez
N
N
Berson
A
A
Kaybanda
M
M
Molina
T
T
Briand
P
P
Haddada
H
H
Guillet
J G
JG
Antoine
B
B
Viguier
M
M
Kahn
A
A
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D019496:Cancer Vaccines / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000517:prevention & control*; D014161:Transduction, Genetic
D000952:Antigens, Polyomavirus Transforming; D019496:Cancer Vaccines