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Dendiric Cell-Based Vaccination With Idiotype For Amyloidosis And Post-Transplant Myeloma
By Martha Q. Lacy, M.D., Mayo Clinic
Multiple myeloma and primary systemic amyloidosis are malignancies of bone marrow plasma cells. Despite recent advances in chemotherapy and stem cell transplantation techniques, both disorders are currently not curable. The majority of patients with these diseases have a monoclonal protein detectable in the blood, which serves as a specific marker of the plasma cell malignancy. This idiotypic monoclonal protein is not found on the surface of mature myeloma cells, but is present on the surface of less mature precursor B-cells. A possible mechanism of relapse after transplant is that these precursor B-cells which have surface idiotype have not been eliminated. Extensive pre-clinical and clinical experience indicates that surface idiotype on myeloma cells and their precursors may be an excellent target for attempted immunotherapy.

We propose to vaccinate patients against the myeloma idiotypic protein by exposing dendritic cells (DCs) to the monoclonal protein obtained from the blood. DCs take up the idiotypic protein, re-express it at the surface and then trigger T cells to attack myeloma cells. We decided to target patients who have already achieved a good response to bone marrow or stem cell transplant with the rationale that immunologic therapies are most likely to be of benefit when myeloma burden is low. Approximately sixty days after completing transplant, patients will undergo leukopheresis. Using buoyant density gradient separation, a population of cells riched for dentritic cells will be collected. The DCs will be incubated with monoclonal protein obtained from the patient's blood for 40 hours. The antigen-loaded DCs will then be re-infused into the patient. This process will be repeated three more times over 4 months (in weeks 0, 2, and 4 followed by a booster in week 16). It is hoped that the resulting potent immune response will reduce myeloma cell tumor load. Patients will be assessed for clinical response. In addition, a series of detailed assays are planned to detect immunologic responses: 1) T- cell proliferation in response to the idiotypic monoclonal protein, 2) release of cytokines such as alpha- Interferon and Interleukin-4 by Elispot assays to assess Th1 versus TH2 responses, 3) testing for a specific cytotoxic T-cell response to idiotype using Elispot for a CD8+T- cells, 4) epitope mapping of the idiotypic protein to determine the specific sequences which elicit the immune response, and 5) DC phenotypic expression and function in response to varying concentrations of GM-CSF.

The development of autologous stem cell transplant techniques has significantly impacted the treatment of myeloma and amyloidosis, but unfortunately has not been shown to be curative. This fact highlights the inadequacy of conventional approaches to treatment and stresses the need to develop new strategies. The approach used here takes advantage of the fact that a myeloma specific protein is readily available for these patients. Dendritic cell vaccination offers the possibility of harnessing the immune system to fight their plasma cell neoplasms. If this approach is successful, it may be applicable for treating all stages of these diseases and may even be useful in preventing development of myeloma in patients with MGUS.
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