In an attempt to induce potent immune antitumor activities, we investigated, within the rat 9L
gliosarcoma model, distal therapeutic vaccinations associating three
therapies: dendritic cell vaccination, intratumoral
granulocyte macrophage colony-stimulating factor (
GM-CSF) gene transfer, and
tumor apoptosis induction.
Vaccines of dendritic cells coinjected with processed
GM-CSF secreting 9L cells induced systemic responses, resulting in the complete regression of distant preimplanted 9L
tumor masses in, with the best strategy, 94% of male rats. All of the cured rats developed a long-term resistance to a rechallenge with parental cells. The curative responses were correlated with the detection of elevated specific cytotoxic activities and a CD4+, CD8+ T cell-, and natural killer (NK) cell-mediated IFN-gamma production. The survival rate of the rat seemed more directly linked to the amount of
GM-CSF secreted by the transduced
tumor cells, which in turn depended on the toxicity of the apoptosis-inducing treatment, than to the level of apoptosis induced. Unexpectedly, alive
GM-CSF secreting 9L cells became apoptotic when injected in vivo. Thus we documented the positive role of apoptosis in the induction of therapeutic antitumor responses by comparing, at equal
GM-CSF exogenous supply, the effects of dendritic cells coinjected with apoptotic or necrotic 9L cells. The data showed the superior therapeutic efficiency of
combined vaccines containing apoptotic
tumor cells. In conclusion, vaccinations with dendritic cells associated with apoptotic
tumor cells secreting
GM-CSF show a very high therapeutic potency that should show promise for the treatment of human
cancer.