Objectives: 1) To establish a mouse model for immunotherapy of multiple myeloma (MM) by adoptive transfer of myeloma-specific CD4+ T cells. 2) To characterize the cellular and molecular basis for rejection of MM by CD4+ T cells. Background: Adoptive immunotherapy has shown promising results for the treatment of melanoma patients and should be applicable for other types of cancer like MM. Adoptive immunotherapy consists in the isolation of antigen-specific T cells, their ex vivo expansion and activation, and subsequent autologous administration. We have started to establish a mouse model for immunotherapy of MM by transfer of CD4+ T cells (Corthay & Bogen, unpublished data). We have also recently developed a novel strategy to study in vivo the very initial events of MM recognition and rejection by CD4+ T cells (Corthay et al, 2005, Immunity in press). We are now planning to use this method to characterize the elimination of MM by CD4+ T cells in a therapeutic setting. Novelty: This is, to our knowledge, the first study of successful immunotherapy of MM by transfer of CD4+ T cells. The mechanisms of myeloma rejection by CD4+ T cells are not know. Such knowledge should be very helpful for defining the conditions for optimal immunotherapy of MM patients.