Alternative pathways of cell death to circumvent pleiotropic resistance in myeloma cells: role of cytotoxic T-lymphocytes.

Pleiotropic resistance to treatment remains one of the major reasons for therapeutic failures in patients with multiple myeloma. Myeloma cells are frequently resistant to physiological inducers of cell death prior to chemotherapy. Moreover, in the course of treatment cells acquire a multidrug resistant (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 cells. This review discusses evidence that cytokine-expressing autologous tumor cell vaccine may be an efficient tool for elimination of both intrinsically resistant myeloma cells as well as cells with acquired MDR in murine models. The vaccine was similarly potent against wild type cells that were resistant to several death receptor ligands, and their isogenic sublines selected for P-glycoprotein-mediated MDR. The anti-myeloma effect of the vaccine was mediated by granzyme B/perforin-secreting cytotoxic T-lymphocytes. This is an example of therapeutic strategy directed at utilizing death pathways that are preserved in pleiotropically resistant tumor cells.