High dose therapy and autologous or allogeneic hematopoietic cell transplantation has proven to be effective therapy for patients with multiple myeloma. However, with both forms of therapy, there is a continuous relapse risk. We propose to treat patients with multiple myeloma using a non-myeloablative mixed chimeric allogeneic transplant along with donor-derived dendritic cells ands idiotype vaccinations. Based upon our prior work we will be using the immunoglobulin idiotype produced by each patient's tumor as the specific antigen along with dendritic cells obtained from the patient's hematopoietic cell donor. Each patient will have the immunoglobulin produced by his/her myeloma cells isolated and purified for use as a vaccine. The patients are treated with sequential autologous and non- myeloablative allogeneic hematopoietic cell transplants. The autologous transplant is used as a cytoreductive step prior to the non- myeloablative allogeneic transplant. The immunosuppressive drugs used to prevent graft-vs-host disease are decreased so that most patients are expected to be off all immunosuppression six months following the allogeneic transplant maneuver. Approximately nine months following the allogeneic transplant procedure, dendritic cells will be obtained by leukapheresis from the donor. These cells will be pulsed with the idiotype protein and then infused into the patient on two occasions, followed by a series of monthly injections of idiotype protein coupled to a carrier protein and mixed with an immunologic adjuvant. The patients will be evaluated for their immune responses against the idiotype protein and signs of graft-versus-host disease. Novel assays will be performed for the detection of cytotoxic T-cells directed against the tumor idiotype. Quantitative PCR will be performed to assess tumor burden. The basic question posed in this project is whether an effective anti- tumor immune response can be induced in patients with multiple myeloma which can augment the therapeutic effect of an allogeneic hematopoietic cell transplant. In this study we will be observing the clinical outcome of the transplant maneuver, as well as molecular correlates of disease, although the proposed initial study is not designed to prove clinical efficacy of the vaccination series. The primary endpoints will be the documentation of immune responses which we hope will be enhanced by allogeneic dendritic cells. If the initial trial shows promising results, appropriate prospective studies will be designed to demonstrate the efficacy of this novel approach.
Showing the most recent 10 out of 307 publications
