Recent clinical studies have demonstrated that dendritic cells are potent antigen presenting cells for induction of immune responses against tumor antigens in human cancer patients. However, widespread evaluation and application of this emerging treatment modality will require a reliable and efficient means to generate sufficient quantities of antigen-loaded dendritic cells for effective patient therapy. The Phase I program has defined a novel single-pass serum-free medium perfusion process for production of highly functional dendritic cells at high inoculum density from patients' leukapheresis cells. This process has been implemented successfully in a closed, manually operated, clinical scale bioreactor system. Feasibility for non-invasive monitoring of the perfusion process by lactate measurement with time during culture has been demonstrated at clinical scale. The primary objectives of the proposed Phase Il studies are to optimize cytokine combinations, medium perfusion rates, material composition and tissue culture treatment of the bioreactor growth surface and oxygen delivery for maximum production of DCs in the clinical scale system. After automation of the process to enhance reliability and reproducibility, DCs generated in the AastromReplicell(TM) System will be evaluated for safety, biodistribution and induction of immune responses against CEA- CAP-1 tumor-peptide antigen under IDE-approved clinical trials at Duke University Medical Center.
A closed, automated, GMP-compliant bioreactor system for dendritic cell derivation, maturation, antigen-loading and harvest would be of great value for immunotherapy of cancer and infectious diseases. The existing methods for derivation of dendritic cells involve multiple open process stems with associated costs in equipment and labor. The development of a fully automated DC culture process will enable widespread application of successful dendritic cell-based immunotherapies in a reliable and cost- effective fashion.
