Phase I Study of Vaccination with Dendritic Cell Myeloma Fusions.

Abstract

We have developed a cancer vaccine in which patient derived myeloma cells are fused with autologous dendritic cells (DCs). In this way, multiple tumor antigens are presented in the context of the immune stimulating machinery of the DC. We are conducting a phase I trial in which patients with multiple myeloma (MM) undergo serial vaccination with DC/myeloma fusions in conjunction with GM-CSF. Eligibility criteria included ≥20% plasma cells in the bone marrow and measurable paraprotein or light chain. To date, 16 patients have been enrolled and 15 have undergone therapy. Patients underwent leukapheresis collection and DCs were generated from adherent mononuclear cells cultured for 5 days with GM-CSF and IL-4 and matured by exposure to TNFa for 48–72 hours. The mean yield of DCs was 1.23 x108 cells with a mean viability of 88%. Patient derived myeloma cells were isolated from bone marrow aspirates. The mean yield of myeloma cells was 92.5 x 106 cells with a mean viability of 90%. Fusion cells were generated by coculture of DCs with myeloma cells in the presence of 50% polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that co-expressed unique DC and myeloma antigens. Mean fusion efficiency and viability was 40% and 84%, respectively. As a measure of immunologic potency, DC/MM fusions stimulated allogeneic T cell proliferation, with mean stimulation indexes of 48, 36, and 9 for the DC, fusion and myeloma cell populations, respectively. To date, 15 patients have completed vaccination at a dose of 1–5x106 fusion cells. Adverse events potentially related to vaccine included injection site reactions, edema, rash, fever (infection), chills, fatigue, muscle aches, pruritis, and diarrhea. One patient with a history of prior deep venous thrombosis (DVT) developed a DVT and pulmonary embolus of uncertain relation to the vaccine. To date, 6/9 evaluable patients have demonstrated immunologic response, defined by at least 2 fold increase in IFNγ expression by CD4 and/or CD8 T cells in response to ex vivo exposure to autologous tumor lysate. Vaccination was associated with an increase in circulating tumor specific T cells as evidenced by an increase in CD8+ cells binding the MUC1 tetramer. The impact of vaccination on circulating levels of regulatory T cells is being examined. Humoral immune responses are being assessed by SERAX analysis. Three patients have ongoing stable disease at 3.5, 6, and 19 months following their initial vaccination. Six patients demonstrated disease stability with subsequent progression ranging from 9 weeks to 8 months following their first vaccine. Vaccination with DC/MM fusions has been well tolerated, associated with immunologic response, and disease stabilization in a majority of patients with multiple myeloma.