Multiple myeloma (MM) is a B-cell malignancy that remains incurable in most patients. After treatment with high-dose chemotherapy and autologous stem-cell support, complete remission rates of 50% are achieved. However, relapses are inevitable in most patients. Additional measures are needed after transplantation to eliminate minimal residual disease, and immunotherapy is an appealing option for this purpose. We hypothesize that optimized dendritic cell (DC)-based immunotherapies are able to elicit a strong myeloma-specific cytotoxic immune response in immunocompetent patients that may effectively control or even eradicate residual tumor cells. Compared to idiotype protein (Id), myeloma cells contain a multitude of tumor antigens that can stimulate an increased repertoire of anti-tumor T cells. Indeed, our preliminary results demonstrate that myeloma lysate-specific T cells are promising effector cells for immunotherapy. In this project, we propose to examine the efficacy of intranodal vaccination of myeloma patients with tumor antigen-pulsed, CD40L-conditioned mature DCs. Newly diagnosed, untreated patients (most of who have nearly intact immune systems) will be targeted, and DC vaccines will be given to the patients prior to and after high-dose therapy in order to achieve a maximal tumor reduction without compromising the effects of immunotherapy. Thus, aim 1 of this project is to evaluate anti-tumor immune and clinical responses in patients receiving Id versus tumor lysate-pulsed DCs, to determine whether tumor lysate-pulsed DCs induce stronger responses. Antigens and keyhole limpet hemocyanin (KLH)-pulsed, CD40L-matured DCs will be used as the vaccine. CD40L-conditioned/matured DCs can activate CD8+ T cells directly and break T-cell tolerance.
In Aim 2, we will evaluate whether re-infusion of blood T cells collected after initial DC vaccination helps to further expand specific T cells in vivo.
Aim 3 is to evaluate whether long-term booster immunization could further augment anti-tumor immune and clinical responses in patients, and aim 4 to elucidate the biological mechanisms of the immunotherapy strategies by examining the induction, number and function of myeloma-specific T cells and subsets in blood and bone marrow of patients and whether immunotherapy may induce epitope spreading and loss of tumor antigens by myeloma cells. Anti-myeloma immunological and clinical responses are the primary and secondary end points of the studies. These innovative approaches will substantially contribute to the ability of immunotherapy to induce or improve long-term survival in patients with MM.
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