Multiple myeloma (MM) is an invariably fatal disease, and there is a great need for better treatment modalities. Idiotype (id) is a well defined tumor-specific antigen, and we and others have shown that id-specific cytotoxic T lymphocytes (CTLs) can lyse myeloma cells in vitro. Id-based immunotherapies have been explored for MM and B-cell lymphoma, and in most of these studies, enhanced id-specific immune responses have been noted, whereas a clinical response could only occasionally be observed in the patients. This may suggest that the enhanced immunity may still be too weak to cause significant tumor destruction and/or a nonbeneficial immune response might have been generated. We hypothesize that id-specific CTLs kill myeloma cells, whereas id-specific T-helper (type-2; Th2) cells may promote myeloma cell growth and survival in vivo. We further hypothesize that a strong tumor-specific cytotoxic immune response established in vivo will effectively suppress or eradicate residual tumor cells, which can be achieved by transfer to patients of a substantial number of ex vivo-generated specific CTLs. Our hypotheses will be tested by generating and characterizing id-specific T cells in myeloma patients, examining their effects on myeloma cells in vitro and in vivo (SCID-hu host), and generating id-specific CTLs to clinical scale for adoptive immunotherapy. We will propagate id-specific T cells of different subsets, such as CD4+ Th1 and Th2 and CD8+ CTLs, from blood and examine T cells from tumor sites, such as bone marrow and focal lesions of patients, for their antigenic specificity, subsets, and function. Lines and clones of id-specific T cells obtained from blood and tumor sites will be tested for their regulatory role on primary myeloma cells in vitro and in the myeloma SCID-hu mouse model. Through these studies, direct evidence will be obtained on whether the different id-specific T cells are able to suppress or promote the growth and survival of primary myeloma cells. This knowledge will be further used to generate CTLs from patients for adoptive immunotherapy. We will define the optimum condition for generating such T cells in vitro and immunize patients to increase the number of specific T cells in vivo before ex vivo propagation. This may also be applied to HLA-matched sibling donors when allogeneic id-specific CTLs should be used for adoptive transfer. These novel approaches will substantially contribute to the ability of immunotherapy to induce or improve long-term survival in patients with MM.