Wilms' tumor protein 1 and cancer/testis antigen 7 expression and immune responses in multiple myeloma

Wilms' tumor protein 1 (WT1) and cancer/testis antigen 7 (CT7) are two myeloma-associated antigens that serve as negative prognostic factors for multiple myeloma (MM). While the emergence of antigen-specific cytotoxic T lymphocytes (CTL) has been correlated with better relapse-free survival after allogeneic stem cell transplantation in patients with myeloid leukemias, little is known about the role of these cells in MM. We sought to characterize WT1 and CT7 protein expression in the bone marrow (BM) of MM patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation (alloTCD-HSCT) followed by donor lymphocyte infusions (DLI), and to examine the significance of WT1- and CT7-specific cellular and humoral immune responses in these patients. We further aimed to identify CT7-derived immunogenic epitopes and their associated allelic restrictions.;Immunohistochemical analyses of WT1 and CT7 protein expression in myeloma BM specimens demonstrated consistent coexpression with CD138 within malignant plasma cells. Longitudinal analyses of 10 patients revealed an association between WT1 and CT7 protein expression in the BM and prognosis.;Following alloTCD-HSCT and DLI, increments in both WT1- and CT7-specific CTL frequencies were observed. These were associated with the reduction or stabilization of specific myeloma markers, in the absence of graft-versus-host disease. Phenotypic analyses revealed enrichment for antigen-specific central memory CTL within the BM, while antigen-specific effector memory CTL dominated in the peripheral blood (PB). The magnitude of the antigen-specific CTL response did not appear dependent on the level of antigen expression within the BM. Moreover, neither type of CTL response was associated with a superior outcome in terms of disease response.;A novel HLA-A*0201-restricted epitope of CT7, FLAMLKNTV, was elucidated. Humoral responses to CT7 were detected in 3/10 patients. Epitope-specific analyses revealed antibody titers to 2/110 CT7 peptides in one patient, with durable responses occurring against both peptides.;Our results suggest an association between the emergence of WT1- and CT7-specific CTL and graft-versus-myeloma effect in patients treated for relapsed MM after alloTCD-HSCT and DLI. These findings support the development of immunotherapeutic approaches targeting WT1 and CT7 for the treatment of MM.