CD28: a novel therapeutic target for the treatment of multiple myeloma (66.10)

Abstract

Abstract Multiple myeloma (MM) is a plasma cell neoplasm which resides in the bone marrow (BM) and is critically dependent upon the BM microenvironment (BMM) for its survival. It has been observed that CD28 is expressed on MM cells and that expression levels correlate with worsening progression and worse prognosis. We have also observed that ligation of CD28 protects MM from chemotherapy. Taken together, these data imply that CD28 is a critical pro-survival molecule for the MM. The ligands for CD28, CD80 and CD86, are expressed on antigen-presenting cells, particularly dendritic cells (DC). We have observed that DCs infiltrate myelomatous portions of patient BM biopsies. We therefore hypothesize that it is the DC in the BMM which is providing the pro-survival signal to the MM via a CD28:CD80/86 interaction. Co-culture of murine or human DC with MM increased MM survival in melphalan. We then treated MM/DC co-cultures with CTLA4-Ig (which blocks CD80/86) and cultured them with or without melphalan. In the presence of melphalan, DC alone increased the survival of MM cells from 30% to 75%; however, addition of CTLA4-Ig completely abrogated this protection. We observed similar results using a CD28 blocking antibody rather than CTLA4-Ig. Mechanistically, such pro-survival signals often involve regulation of apoptosis. We have preliminary data which suggest that CD28 ligation decreases the levels of the pro-apoptotic molecule Bim, suggesting a mechanism for CD28-mediated survival.