Chemoimmunomodulation with antineoplastic agents and generation of dendritic cell vaccine

Abstract

We have previously observed that ultra-low concentrations of several antineoplastic agents are able to up-regulate the activity of dendritic cells (DC), as well as modify the transcription of a variety of genes of tumor cells, which seems to induce increased immunogenicity on these cells. Among the genes, which transcription was modified by paclitaxel, we cite those associated with the antigen processing machinery (APM components) and heat sock proteins (HSP). Now, we have to investigate whether other drugs, which immunomodulatory potential was previously observed, are also able to increase the immunogenicity of tumor cells. Besides, under the clinical point of view, we should consider that the association of DC vaccines with minimal effective dose (MED) of such drugs could be better than using just the immunomodulatory doses, since most of tumor cells are able to develop different escape mechanims to evade the immune system. Our hypothesis is that if the treatment is able to increase the expression of immunogenic molecules, the transfection of DC with mRNA of such tumor cells could be an efficient strategy for the generation of DC vaccine. Finally, we have to evaluate whether the in vitro findings have a correspondent in vivo efficiency, before testing the protocol with cells from patients. Therefore, this project was designed to verify : a) the effect of nontoxic concentration or MED of paclitaxel, 5-aza-2-deoxycytidin and 5-fluorouracil+leucovorin on DC; b) the feasiblility of using mRNA of drug-treated tumor cells for the preparation of DC vaccine; c) whether the increased immunogenicity induced by pre-treatment is associated with expression of HSPs, and d) whether the in vitro results have correspondent in vivo protective effect in a murine model of colon cancer. (AU)