Alternative pathways of cell death to circumvent pleiotropic resistance inmyeloma cells: Role of cytotoxic T-lymphocytes

Pleiotropic resistance to treatment remains one of the major reasons for th erapeutic failures in patients with multiple myeloma. Myeloma cells are fre quently resistant to physiological inducers of cell death prior to chemothe rapy. Moreover, in the course of treatment cells acquire a multidrug resist ant (MDR) phenotype, making eradication of the tumor even more difficult. A necessary prerequisite for circumventing complex pleiotropic resistance is therefore defining the signaling pathways that execute death in myeloma ce lls. This review discusses evidence that cytokine-expressing autologous tum or cell vaccine may be an efficient tool for elimination of both intrinsica lly resistant myeloma cells as well as cells with acquired MDR in murine mo dels. The vaccine was similarly potent against wild type cells that were re sistant to several death receptor ligands, and their isogenic sublines sele cted for P-glycoprotein-mediated MDR. The anti-myeloma effect of the vaccin e was mediated by granzyme B/perforin-secreting cytotoxic T-lymphocytes. Th is is an example of therapeutic strategy directed at utilizing death pathwa ys that are preserved in pleiotropically resistant tumor cells.