DOES PREVENTIVE VACCINATION WITH ENGINEERED TUMOR-CELLS WORK IN CANCER-PRONE TRANSGENIC MICE

The use of genetically modified tumor cells as vaccines has been succe ssful in numerous animal models of grafted syngenic tumors and has pro vided the groundwork for many clinical trials of gene therapy in cance r patients. To investigate the real efficacy of ex vivo gene therapy-b ased vaccines, we used transgenic mice that express the SV40 large T a nd small t antigens under the control of hepatic antithrombin III (ASV -B)-regulatory sequences. These mice systematically develop hepatocarc inoma. Hepatoma cells, derived from ASV-B transgenic mice, were gene-t ransduced to express either interleukin-2, interleukin-4, the granuloc yte-macrophage colony-stimulating factor, or the T-cell costimulatory molecule B7.1. First, we demonstrated the vaccine potential of enginee red hepatoma cells by immunizing nontransgenic mice with these cells, which prevented the growth of subsequent grafted nontransduced hepatom a cells. However, vaccination of pretumoral transgenic animals with va rious combinations of engineered hepatoma cells failed to inhibit hepa toma onset and progression. Rather, tumor development in ASV-B mice ap pears to be dependent on the immune system, since neonatal induction o f immunotolerance to tumor in ASV-B mice cells was associated with a m oderate, but significant, acceleration of tumor development. These res ults seriously call into question the efficacy of this strategy of act ive vaccinotherapy against natural tumors.