AUTOREGULATORY CIRCUITS IN MYELOMA - TUMOR-CELL CYTOTOXICITY MEDIATEDBY SOLUBLE CD16

Background. Multiple myeloma remains an incurable malignancy due to ma rked resistance of the tumor to standard doses of chemotherapy. Treatm ent approaches, using chemotherapeutic dose escalation and hematopoiet ic stem cell support have resulted in significant augmentation of tumo r mass reduction such that complete remissions are effected in similar to 50% of patients, These remissions are, however, often not durable. In the setting of minimal residual disease, therefore, adjuctive immu notherapy may be useful. Methods. Peripheral blood mononuclear cells w ere studied from 28 untreated patients with multiple myeloma (MM). Mon onuclear cell CD16 (FcR gamma III) expression was determined by flow c ytometry. The effect of lymphocyte-derived soluble CD16, isolated by a ffinity chromatography, on MM cell growth and differentiation was asse ssed, MM cell proliferation, viability, immunoglobulin production and gene expression was studied. Results. Data are presented indicating th at cells expressing CD16 are increased in untreated patients with IgG- secreting myeloma. The predominant phenotype of these cells is CD8(+) or CD56(+). These CD16(+) cells can produce a soluble form of the Fc r eceptor (sFcR, sCD16) that can bind to surface Ig on cultured human Ig G-secreting myeloma cells and effect suppression of tumor cell growth and Ig secretion. This effector function is accompanied by concomitant suppression of c-myc as well as IgH and IgL gene transcription. Final ly, prolonged exposure to sCD16 causes myeloma tumor cell cytolysis. C onclusions. sCD16 and possibly other soluble FcR are candidate molecul es for adjunctive immunotherapy of myeloma, once complete responses ha ve been effected by intensive cytotoxic therapy, now possible in up to 50% of newly diagnosed patients.