Vaccination with Dendritic Cell Myeloma Fusions Alone or in Conjunction with Stem Cell Transplantation for Patients with Multiple Myeloma.

Abstract

Multiple myeloma expresses unique antigens that potentially serve as targets for tumor specific immunotherapy. Dendritic cells (DCs) are the most potent antigen presenting cells that prominently express costimulatory molecules and are uniquely able to stimulate anti-tumor immune responses. We have developed a promising cancer vaccine in which patient derived myeloma cells are fused with autologous DC resulting in the presentation of a broad array of tumor antigens in the context of DC mediated costimulation. DC/myeloma fusions potently stimulate anti-tumor immune responses in vitro as manifested by the lysis of autologous tumor targets. We are currently conducting phase I clinical trials in which patients with myeloma undergo serial vaccination with DC/myeloma fusions alone or in conjunction with stem cell transplantation. GM-CSF (100 μg) was administered subcutaneously on the day of vaccination and for 3 days thereafter. To date, 18 patients have been enrolled (11- vaccine alone, 7 vaccine transplant). To generate mature DCs, adherent mononuclear cells were isolated from a leukapharesis collection, cultured for 5 days with GM-CSF and IL-4 and terminal maturation was induced by exposure to TNFa for 48–72 hours. DCs prominently expressed HLA class II, costimulatory and maturation markers. The mean yield and viability of the DC preparations was 1.5 x 108 cells and 88%, respectively. Patient derived myeloma cells were isolated from bone marrow aspirates and were quantified by the expression of CD38 and/or CD138. The mean yield and viability of the myeloma cell collections was 7.3 x 107 cells and 89%, respectively. Fusion cells were generated by coculture of DCs with myeloma cells at a 3:1–10:1 ratio 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 of the fusion cell preparation was 40% and 84%, respectively. As a measure of immunologic potency, fusion cells prominently stimulated allogeneic T cell proliferation. To date, 13 patients have completed vaccination at a dose of 1–5 x 106 fusion cells. Adverse events judged to be potentially vaccine related have included vaccine 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, 4/6 evaluable patients have demonstrated evidence of vaccine induced anti-myeloma immunity as demonstrated 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. Of patients undergoing vaccine therapy alone, 5 patients demonstrated stabilization of the myeloma paraprotein for 2–6 months following initiation of vaccination. Of 3 patients completing post-transplant vaccination, 1 patient demonstrated resolution of the persisting myeloma protein post-transplant, 1 patient exhibited stable post-transplant paraprotein levels for 6 months, and 1 patient demonstrated a transient increase followed by a progressive decline in paraprotein levels post-transplant.